OAE Publishing Inc.

The Journal of Cardiovascular Aging

Published by OAE Publishing Inc. and International Academy of Cardiovascular Sciences

Online ISSN: 2768-5993

Disciplines: Biochemistry, Genetics and Molecular, Medicine

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Figure 1. Mitochondrial respiration measurements in segments from thoracic aorta. OCR measurements over time (A), basal respiration (B), ATP-linked (C) and maximal respiration (D), and spare respiratory capacity (E) analyzed by 2-way ANOVA. OCR: Oxygen consumption rate; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 2. In vivo vascular function measurements. Arterial stiffness (A) and example picture of pulse wave velocity measurement in abdominal aorta (B). Laser Doppler measurements describing AUC (C) and maximal response (D). Ex vivo histological analysis of carotid arteries to assess collagen content (E) and elastin breaks (F). The 2-way ANOVA with *significant effect of genotype and # significant effect of SUL-238 with P < 0.05. AUC: Area under the curve; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 3. Ex vivo vascular function measured in thoracic aorta: endothelium-dependent vasodilation (A), endothelium-independent vasodilation (B), relative NO contribution to endothelium-dependent vasodilation in WT and SMC-KO animals (C), NO contribution to vasodilation in SMC-KO animals (D) and logEC50 of the curves from D (E), NO contribution in WT animals (F). Analyzed with GLM (all except for C and E) or 2-way ANOVA for C and E with *significant effect of genotype, # significant effect of SUL-238, and $ significant effect of pathway inhibitor with P < 0.05. NO: Nitric oxide; WT: wild-type littermates; GLM: generalized linear model; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 4. Ex vivo vascular function measured in thoracic aorta: EDH contribution in SMC-KO animals -IK Ca /SK Ca channels (A) and BK Ca channels (B) to endothelium-dependent vasodilation, relative EDH contribution to vasodilation (C), EDH contribution in WT animals (D), and endothelium-dependent vasodilation in mesenteric arteries (E). Analyzed with GLM (all except for C) or 2-way ANOVA (C) with *significant effect of genotype, # significant effect of SUL-238, and $ significant effect of inhibitor with P < 0.05. EDH: Endotheliumderived hyperpolarization; WT: wild-type littermates; GLM: generalized linear model; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 5. The p16 and p21 protein abundances in abdominal aorta (A-B). mRNA expression of SASP factors, senescence and kidney injury markers in the kidney (C-H). Analyzed with 2-way ANOVA with *significant effect of genotype and # significant effect of SUL-238 with P < 0.05. SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
The modified 6-chromanol SUL-238 protects against accelerated vascular aging in vascular smooth muscle Ercc1 -deficient mice

October 2024

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45 Reads

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Janette van der Linden

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Anton J. M. Roks
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Aims and scope


To establish The Journal of Cardiovascular Aging as a premier, most desirable, and entirely transparent international platform for dissemination of the state-of-the-art basic, translational, and clinical studies in aging and cardiovascular disease. The journal aims to publish state-of-the-art scientific discoveries pertaining to the broad spectrum of cardiovascular consequences of aging. The Editors aim to provide timely, fair, and balanced considerations to all manuscripts submitted and seek the opinions of the external experts in prioritizing the meritorious manuscripts.

The Journal of Cardiovascular Aging aims to publish clinical, translational, and basic science discoveries that pertain to all aspects of aging and cardiovascular disease. All aspects of basic and clinical sciences relating to aging in the context of cardiovascular disease are considered to be within the scope of the journal. Examples include clinical trials, diet, treatment, genetics, epigenetics, genomics, stem cells, immunology, inflammation, cell cycle regulation, senescence, signaling pathways, and pharmacology, among others. The primary focus of the journal is to publish original research articles that provide novel insights into cardiovascular aging. Studies confirming and validating previous findings, whenever providing unequivocal findings, are also within the scope of the journal. Review manuscripts on topics of broad interest to the readership of the journal, Editorials, and Commentaries on timely and important topics will also be considered.

Recent articles


Figure 1. Mitochondrial respiration measurements in segments from thoracic aorta. OCR measurements over time (A), basal respiration (B), ATP-linked (C) and maximal respiration (D), and spare respiratory capacity (E) analyzed by 2-way ANOVA. OCR: Oxygen consumption rate; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 2. In vivo vascular function measurements. Arterial stiffness (A) and example picture of pulse wave velocity measurement in abdominal aorta (B). Laser Doppler measurements describing AUC (C) and maximal response (D). Ex vivo histological analysis of carotid arteries to assess collagen content (E) and elastin breaks (F). The 2-way ANOVA with *significant effect of genotype and # significant effect of SUL-238 with P < 0.05. AUC: Area under the curve; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 3. Ex vivo vascular function measured in thoracic aorta: endothelium-dependent vasodilation (A), endothelium-independent vasodilation (B), relative NO contribution to endothelium-dependent vasodilation in WT and SMC-KO animals (C), NO contribution to vasodilation in SMC-KO animals (D) and logEC50 of the curves from D (E), NO contribution in WT animals (F). Analyzed with GLM (all except for C and E) or 2-way ANOVA for C and E with *significant effect of genotype, # significant effect of SUL-238, and $ significant effect of pathway inhibitor with P < 0.05. NO: Nitric oxide; WT: wild-type littermates; GLM: generalized linear model; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 4. Ex vivo vascular function measured in thoracic aorta: EDH contribution in SMC-KO animals -IK Ca /SK Ca channels (A) and BK Ca channels (B) to endothelium-dependent vasodilation, relative EDH contribution to vasodilation (C), EDH contribution in WT animals (D), and endothelium-dependent vasodilation in mesenteric arteries (E). Analyzed with GLM (all except for C) or 2-way ANOVA (C) with *significant effect of genotype, # significant effect of SUL-238, and $ significant effect of inhibitor with P < 0.05. EDH: Endotheliumderived hyperpolarization; WT: wild-type littermates; GLM: generalized linear model; SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
Figure 5. The p16 and p21 protein abundances in abdominal aorta (A-B). mRNA expression of SASP factors, senescence and kidney injury markers in the kidney (C-H). Analyzed with 2-way ANOVA with *significant effect of genotype and # significant effect of SUL-238 with P < 0.05. SMC-KO: DNA repair endonuclease Ercc1 knockout in vascular smooth muscle cells.
The modified 6-chromanol SUL-238 protects against accelerated vascular aging in vascular smooth muscle Ercc1 -deficient mice
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October 2024

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45 Reads

Introduction: Vascular aging is marked by increased mitochondrial reactive oxygen species (ROS) production, which leads to decreased nitric oxide (NO)-mediated vasodilation. Loss of NO can be partially compensated by endothelium-derived hyperpolarization (EDH), which partly relies on increased mitochondrial Ca2+ release to maintain vascular dilation. Thus, intervention in mitochondria may target both NO and EDH signaling to alleviate aging-related vascular dysfunction. DNA damage by mitochondrial ROS is an important cause of organismal aging. Previous work showed that local vascular Ercc1 knockout dramatically accelerates vascular aging. The aim of the study was to investigate the effect of chronic treatment with the modified 6-chromanol, SUL-238, an inhibitor of mitochondrial reverse electron flux and ROS, in a mouse model of accelerated vascular smooth muscle aging induced by DNA repair endonuclease Ercc1 knockout (SMC-KO). Aim: The aim of the study was to investigate the effect of chronic treatment with the modified 6-chromanol, SUL-238, an inhibitor of mitochondrial reverse electron flux and ROS, in a mouse model of accelerated vascular smooth muscle aging induced by DNA repair endonuclease Ercc1 knockout (SMC-KO). Methods: SMC-KO mice and healthy wild-type littermates received SUL-238 (90 mg/kg/day) in drinking water from 12 to 22 weeks of age. At the age of 21 weeks, arterial stiffness was measured in vivo with echography and they were euthanized at the age of 22 weeks. Ex vivo vascular function was assessed in wire myography setups and mitochondrial function of the thoracic aorta was assessed using a seahorse assay. Results: SMC-KO mice showed reduced EDH-mediated vasodilation, elevated arterial stiffness, and increased elastin breaks at 22 weeks of age compared to their wild-type littermates. SUL-238 improved EDH, thus restoring aortic and mesenteric relaxation in SMC-KO mice. Furthermore, the number of elastin breaks was reduced and arterial stiffness normalized after treating SMC-KO mice with SUL-238. Mitochondrial respiration measured in the aorta was not different between the groups. Conclusion: Chronic treatment with SUL-238 alleviates features of vascular aging, including decreased vasodilation and increased arterial stiffness. SUL-238 seems to have a more general effect on aging rather than involving a direct coupling between mitochondrial function and vascular signaling. SUL-238 is the first small-molecule drug reported to increase EDH after chronic treatment.


Figure 1. Aging in engineered cardiovascular tissues. Dox: Doxorubicin; HGPS: hutchinson-gilford progeria syndrome; hCB-EPC: human cord blood-derived endothelial progenitor cells; iPSC: induced pluripotent stem cell; iCM: iPSC-derived cardiomyocyte; iSMC: iPSCderived smooth muscle cells; NRCM: neonatal rat cardiomyocyte; ROS: reactive oxygen species; TEBV: tissue-engineered blood vessels.
Figure 2. Rejuvenation of cardiovascular tissues. CDC: Cardiosphere-derived cell; GDM: gestational diabetes mellitus; MI: myocardial infarction; MSC: mesenchymal stem cell; ECFC: endothelial colony-forming cells.
Features of aging in engineered cardiovascular tissues
Rejuvenation in cardiovascular tissues
Aging and rejuvenation of engineered cardiovascular tissues: from research to clinical application

October 2024

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10 Reads

Aging is a key contributor to the pathogenesis of cardiovascular diseases (CVDs). However, current methods and models of CVD do not include the factor of aging due to the use of premature cardiomyocytes. There is an urgent need for an engineered cardiovascular tissue (ECT) model that includes aging as the greatest CVD risk factor to facilitate drug development for aged CVD patients. Cell therapy, which transplants pluripotent stem cell-derived cardiomyocytes in patients, was proved to be effective for cardiac repair, while the cell retention rate is limited. Alternatively, implantation of ECT could enable long-term retention of cells after translation and may result in rejuvenation in aged hearts. This review summarizes the key features of aging and the influencing factors in engineered cardiovascular tissues. The applications and challenges of engineered myocardium designed for clinical use are also discussed.


Cardiomyocyte senescence. Upstream stressors such as aging, ischemia, ischemia/reperfusion, and doxorubicin activate the DNA damage response/p53 and p16 signaling, which in turn leads to cardiomyocyte senescence. Senescent cardiomyocytes feature enlarged cell size, increased levels of p16, p21, and γH2AX, increased senescence-associated β-galactosidase (SA-β-gal) activity, and the senescence-associated secretory phenotype (SASP). The accumulation of senescent cardiomyocytes in the heart results in cardiac hypertrophy, fibrosis, and dysfunction. The figure was generated with BioRender.com.
Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart

May 2024

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46 Reads

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1 Citation

Cellular senescence in cardiomyocytes, characterized by cell cycle arrest, resistance to apoptosis, and the senescence-associated secretory phenotype, occurs during aging and in response to various stresses, such as hypoxia/reoxygenation, ischemia/reperfusion, myocardial infarction (MI), pressure overload, doxorubicin treatment, angiotensin II, diabetes, and thoracic irradiation. Senescence in the heart has both beneficial and detrimental effects. Premature senescence of myofibroblasts has salutary effects during MI and pressure overload. On the other hand, persistent activation of senescence in cardiomyocytes precipitates cardiac dysfunction and adverse remodeling through paracrine mechanisms during MI, myocardial ischemia/reperfusion, aging, and doxorubicin-induced cardiomyopathy. Given the adverse roles of senescence in many conditions, specific removal of senescent cells, i.e., senolysis, is of great interest. Senolysis can be achieved using senolytic drugs (such as Navitoclax, Dasatinib, and Quercetin), pharmacogenetic approaches (including INK-ATTAC and AP20187, p16-3MR and Ganciclovir, p16 ablation, and p16-LOX-ATTAC and Cre), and immunogenetic interventions (CAR T cells or senolytic vaccination). In order to enhance the specificity and decrease the off-target effects of senolytic approaches, investigation into the mechanisms through which cardiomyocytes develop and/or maintain the senescent state is needed.


The role of brown adipose tissue in mediating healthful longevity

April 2024

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87 Reads

There are two major subtypes of adipose tissue, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT). It has been known for a long time that WAT mediates obesity and impairs healthful longevity. More recently, interest has focused on BAT, which, unlike WAT, actually augments healthful aging. The goal of this review is to examine the role of BAT in mediating healthful longevity. A major role for BAT and its related beige adipose tissue is thermogenesis, as a mechanism to maintain body temperature by producing heat through uncoupling protein 1 (UCP1) or through UCP1-independent thermogenic pathways. Our hypothesis is that healthful longevity is, in part, mediated by BAT. BAT protects against the major causes of impaired healthful longevity, i.e., obesity, diabetes, cardiovascular disorders, cancer, Alzheimer’s disease, reduced exercise tolerance, and impaired blood flow. Several genetically engineered mouse models have shown that BAT enhances healthful aging and that their BAT is more potent than wild-type (WT) BAT. For example, when BAT, which increases longevity and exercise performance in mice with disruption of the regulator of G protein signaling 14 (RGS14), is transplanted to WT mice, their exercise capacity is enhanced at 3 days after BAT transplantation, whereas BAT transplantation from WT to WT mice also resulted in increased exercise performance, but only at 8 weeks after transplantation. In view of the ability of BAT to mediate healthful longevity, it is likely that a pharmaceutical analog of BAT will become a novel therapeutic modality.


Targeting vascular senescence in cardiovascular disease with aging

February 2024

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17 Reads

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2 Citations

Aging is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Two major age-associated arterial phenotypes, endothelial dysfunction and large elastic arterial stiffness, are autonomous predictors of future CVD diagnosis and contribute to the progression of CVD in older adults. Senescent cells lose the capacity to proliferate but remain metabolically active and secrete inflammatory factors termed senescence-associated secretory phenotype (SASP), leading to an increase in inflammation and oxidative stress. Accumulation of senescent cells is linked with the progression of age-related diseases and has been known to play a role in cardiovascular disease. In this brief review, we describe the characteristics and mechanisms of senescent cell accumulation and how senescent cells promote endothelial dysfunction and arterial stiffness. We focus on a range of novel therapeutic strategies aimed at reducing the burden of endothelial dysfunction leading to atherosclerosis through targeting senescent cells. Studies have begun to investigate a specific class of drugs that are able to selectively eliminate senescent cells, termed senolytics, which have shown great promise in reversing the aging phenotype and ameliorating pathologies in age-related disorders, creating a new opportunity for aging research. Generating therapies targeting the elimination of senescent cells would improve health span and increase longevity, making senolytics a promising therapy for cardiovascular diseases.



Main mitochondrial alterations in cardiovascular aging.
Dysfunctional mitochondria elicit bioenergetic decline in the aged heart

February 2024

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143 Reads

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1 Citation

Aging represents a complex biological progression affecting the entire body, marked by a gradual decline in tissue function, rendering organs more susceptible to stress and diseases. The human heart holds significant importance in this context, as its aging process poses life-threatening risks. It entails macroscopic morphological shifts and biochemical changes that collectively contribute to diminished cardiac function. Among the numerous pivotal factors in aging, mitochondria play a critical role, intersecting with various molecular pathways and housing several aging-related agents. In this comprehensive review, we provide an updated overview of the functional role of mitochondria in cardiac aging.


Extracellular vesicles: the key to unlocking mechanisms of age-related vascular disease?

February 2024

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116 Reads

Aging is associated with the development of two ubiquitous, detrimental pathologies, vascular calcification and amyloidosis. These pathologies are characterized by the accumulation of toxic aggregates in the vessel extracellular matrix (ECM) in the form of crystalline calcium and phosphate mineral or insoluble protein fibrils, respectively. These aggregates impact ECM integrity, drive vascular stiffening, and can also cause cell death and phenotypic change in the cells that interact with them. The deposition of both calcification and amyloid requires a nucleus that can mediate the mineralization of calcium and phosphate, or amyloid aggregation from precursor proteins or peptides. Emerging evidence suggests that changes in the composition of the ECM associated with cellular senescence, as well as extracellular vesicle (EV) release, cargo-loading, trapping, and aggregation within the ECM, are common and synergistic mechanisms that regulate the development of these pathologies. Importantly, vascular smooth muscle cells (VSMCs) orchestrate the formation of both pathologies that commonly co-occur in the aging vasculature. Here, we outline the commonalities and differences in what is known about the genesis of calcification and amyloid, and highlight key questions and areas that remain unknown and require further investigation. The complex relationship between senescence, EVs, and the ECM, mediated by VSMCs, which drives the accumulation of HA and amyloid, could be a target for therapeutic intervention.


HIF2A is necessary for hypoxia-mediated cardiomyocyte proliferation. (A) qPCR for HIF1A and HIF2A in control and MCM;HIF1Af/f or HIF2Af/f mice, respectively, in normoxia. (B) Quantification of pH3+ cardiomyocytes in hypoxia-exposed control, Myh6-MCM;HIF1Af/f, and Myh6-MCM;HIF2Af/f mice. (C) Representative image of pH3-labeled cardiomyocyte nucleus (white arrow) in Myh6-MCM;HIF2Af/f. (Scale bar 10 µm). (D) TUNEL staining quantification in the hearts of control, Myh6-MCM;HIF1Af/f, and Myh6-MCM;HIF2Af/f mice placed in chronic hypoxia. (E) Genetic model used for HIF2A-OE experiments. (F) qPCR for human HIF2A in control and MCM;HIF2A-OE hearts, relative to 18 S. (G) Heart weight-body weight ratio (mg/g) of control and MCM;HIF2A-OE mice. (H-I) Cardiac function assessed by EF and FS of control and MCM;HIF2A-OE mice. (J) Average cardiomyocyte cell size determined by WGA quantification of control and MCM;HIF2A-OE mice. (K) Mean number of isolated cardiomyocytes digested from control and MCM;HIF2A-OE hearts. (L) Representative cell pellets derived upon digestion of control and MCM;HIF2A-OE hearts. pH3: Phosphorylated histone H3; EF: ejection fraction; FS: fractional shortening; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; OE: overexpression; WGA: wheat germ agglutinin. Each dot represents one biological replicate.
Ectopic HIF2A promotes cardiomyocyte proliferation and improves cardiac function after injury. (A and B) Representative pH3+ cardiomyocyte nucleus (white arrow) from a MCM;HIF2A-OE heart and quantification (scale bar 10 µm). (C and D) MADM quantification and tissue section images of single-labeled and double-labeled cells from control and MCM;HIF2A-OE tissue sections. Red and green arrows point to single-labeled CMs (scale bar 80 µm). (E and F) Baseline and post-injury ejection fraction of control and MCM;HIF2A-OE mice following adult LAD ligation-induced MI, along with representative M-mode echocardiographic images. (G and H) Mean percent fibrosis in control and MCM;HIF2A-OE hearts 12 weeks after injury using Masson trichrome staining and representative cross-sectional images. (I and J) Cell size in control and MCM;HIF2A-OE hearts 12 weeks after MI using WGA staining, along with representative images. MADM: Mosaic analysis with double markers; LAD: left anterior descending artery; OE: overexpression. Each dot represents one biological replicate. *P < 0.05 by unpaired t test in (E).
Ectopic HIF2A is associated with less DNA damage. (A) Gene ontology analysis by Gorilla algorithm shows pathways that are significantly upregulated in MCM;HIF2A-OE relative to control hearts. Reg/of: Regulation of; NT: nucleotide; ROS: reactive oxygen species; Org: organic; OH: hydroxy; cat: catabolic. (B) Gene Set Enrichment Analysis (GSEA) shows that pathways associated with DNA damage and repair are upregulated in the control hearts. Zero cross is at 9014. Top: non-homologous end-joining (NHEJ) and bottom: DNA double-strand break response. EF: Enrichment score. (C-G) Quantification and immunoblots of DNA damage-associated proteins in control and MCM;HIF2A-OE hearts. (H and I) Representative immunofluorescent stained cardiac tissue sections and quantification of 8-oxoG nuclei from control and MCM;HIF2A-OE hearts. (J) Proposed schematic for HIF2A mechanism in CMs (created with BioRender.com.) OE: Overexpression; NHEJ: non-homologous end-joining; dsDNA: double stranded DNA; ES: enrichment score.
Hypoxia-induced stabilization of HIF2A promotes cardiomyocyte proliferation by attenuating DNA damage

January 2024

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147 Reads

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3 Citations

Introduction: Gradual exposure to a chronic hypoxic environment leads to cardiomyocyte proliferation and improved cardiac function in mouse models through a reduction in oxidative DNA damage. However, the upstream transcriptional events that link chronic hypoxia to DNA damage have remained obscure. Aim: We sought to determine whether hypoxia signaling mediated by the hypoxia-inducible factor 1 or 2 (HIF1A or HIF2A) underlies the proliferation phenotype that is induced by chronic hypoxia. Methods and Results: We used genetic loss-of-function models using cardiomyocyte-specific HIF1A and HIF2A gene deletions in chronic hypoxia. We additionally characterized a cardiomyocyte-specific HIF2A overexpression mouse model in normoxia during aging and upon injury. We performed transcriptional profiling with RNA-sequencing on cardiac tissue, from which we verified candidates at the protein level. We find that HIF2A - rather than HIF1A - mediates hypoxia-induced cardiomyocyte proliferation. Ectopic, oxygen-insensitive HIF2A expression in cardiomyocytes reveals the cell-autonomous role of HIF2A in cardiomyocyte proliferation. HIF2A overexpression in cardiomyocytes elicits cardiac regeneration and improvement in systolic function after myocardial infarction in adult mice. RNA-sequencing reveals that ectopic HIF2A expression attenuates DNA damage pathways, which was confirmed with immunoblot and immunofluorescence. Conclusion: Our study provides mechanistic insights about a new approach to induce cardiomyocyte renewal and mitigate cardiac injury in the adult mammalian heart. In light of evidence that DNA damage accrues in cardiomyocytes with aging, these findings may help to usher in a new therapeutic approach to overcome such age-related changes and achieve regeneration.


Risk of clinical outcomes according to Lipoprotein(a) levels. Absolute risk per 10,000 person-years according to Lp(a) concentrations. Based on data from 70,286 white individuals in the Copenhagen General Population Study with a median of 7.4 years of follow-up.
Lp(a) and CV diseases. ASCVD: Atherosclerotic cardiovascular disease; CV: cardiovascular; Lp(a): lipoprotein(a); MESA: multi-ethnic study of atherosclerosis.
Effect of lipid-lowering therapies on Lp(a) levels. CEPT: Cholesteryl ester transfer protein; Lp(a): lipoprotein(a); LLT: lipid-lowering therapy; PCSK9: proprotein convertase subtilisin/kexin type 9.
Circulating culprit or therapeutic bullseye: lipoprotein(a) in cardiovascular risk assessment and novel therapeutic prospects

January 2024

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116 Reads

Lipoprotein(a) [Lp(a)] has emerged as a significant player in the realm of cardiovascular disease (CVD), exerting a pivotal role in atherosclerotic cardiovascular disease (ASCVD), aortic valve stenosis (AVS), and overall cardiovascular (CV) and all-cause mortality. Since its discovery in 1963 by Kåre Berg, our understanding of Lp(a) has undergone significant evolution. This comprehensive review delves into the genetics, structure, assembly, and inter-population differences of Lp(a), shedding light on its intricate involvement in CVD. Genetically, Lp(a) is primarily influenced by variations in the LPA gene. The LPA gene encodes apo(a) and the variation in the kringle domains is the main determinant of plasma Lp(a) levels. Other genetic variants, such as SNPs in the LPA gene region, the pentanucleotide repeat polymorphism, and specific SNPs in the coding sequences of kringle domains, have also been associated with varying Lp(a) concentrations. Additionally, genes outside the LPA locus, including APOE, APOH, and CEPT gene regions, contribute to Lp(a) variability across different populations. Inter-population differences in Lp(a) levels are evident, with ethnicity and sex playing significant roles. Racial disparities in median Lp(a) concentration have been observed, with black individuals often displaying higher levels compared to their white counterparts. The review underscores Lp(a) as an independent, heritable CV risk factor in both primary and secondary settings. High Lp(a) levels are closely linked to the recurrence of myocardial infarction, AVS, and CV events. The necessity of measuring Lp(a) concentration at least once in life to assess an individual's absolute global CV risk is emphasized. Despite substantial progress, many questions remain unanswered about Lp(a), including its physiological role in the cardiovascular system and its involvement in inflammatory and thrombotic processes. Ongoing research holds promise for the development of therapeutic interventions, such as pharmacological agents and apheresis, to mitigate the cardiovascular risks associated with elevated Lp(a) levels. This review highlights the multifaceted nature of Lp(a) in the context of cardiovascular health, emphasizing the importance of continued research efforts to unravel its complexities and develop innovative strategies for managing its associated risks.


Schematic diagram differentiating normal hearts from dilated and hypertrophied hearts. Cardiomyopathies occur due to genetic variations, resulting in distinct physiological and/or pathophysiological consequences. In terms of clinical manifestations, cardiomyocytes within hypertrophied hearts become enlarged and demonstrate cardiac dysfunction due to increased left ventricular wall thickness, diminished left ventricular cavity size, and altered blood flow rates. LA-Left Atrium, MV-Mitral Valve, LV-Left Ventricle, LVOTO-Left Ventricular Outflow Tract Obstruction.
Structure and arrangements of myofilament protein in C-zone of cardiac sarcomere. The myofilaments within the sarcomere consist of two types: thick and thin filaments. The thick filaments are primarily composed of myosin protein. Each myosin molecule consists of a heavy chain that forms a tail and terminates with a globular head. Additionally, light chains interact with these globular heads. The giant protein titin spans across the sarcomere and is surrounded by myosin. The thin filaments are constituted by actin, forming a helical structure that interacts with the myosin globular heads. Cardiac myosin binding protein-C (MYBPC3), the cardiac paralog, is a regulatory protein that associates with actin and myosin, binding at its N-terminal and interacting with titin at its C-terminal. The thin filament protein, tropomyosin, wraps around the actin helix, and the three complex subunits of other thin filament proteins, known as cardiac troponins, namely Troponin C (TnC), Troponin T (TnT), and Troponin I (TnI), are also present.
Schematic representation of MYBPC3 gene variant-associated molecular events and age-associated hallmarks triggering hypertrophic signals in cardiac muscles. The nonsense-mediated mRNA degradation, ubiquitin proteosome-mediated protein degradation, alternate splicing, protein phosphorylation, and deregulated calcium sensing are the most common events in the HCM phenotype with MYBPC3 mutations. The hallmarks of aging - namely, genomic instability, inflammation, autophagy, mitochondrial dysfunction, deregulated nutrient sensing, altered cellular senescence, protein homeostasis, and epigenetic alterations - activate aging-associated pathways in cardiac muscle cells. Both genetic mutation and aging-associated events generate pro-hypertrophic signals and induce hypertrophic phenotype affecting the cardiac muscle cell structure and function.
Key regulatory pathways involved in the aging process. Extracellular signals (nutrients, growth factors) and intracellular signals (genomic instability, mitochondrial dysfunction, and oxidative stress) initiate aging-associated signaling events. Cellular glucose uptake acts through the AMPK pathway, while growth factors, insulin, and insulin-like growth factors bind to their respective receptors and transmit signals through the Ras and PI3K-AKT pathways. Similarly, intracellular oxidative stress (ROS) and DNA damage-associated stress signals activate the PI3K, NFκB, SIRT1, and FOXO pathways. These pathways, either directly or through mTORC1, modulate cellular processes (elevated inflammation, reduced cell growth and proliferation rate, and inhibition of autophagy), leading to the aging phenotype.
Potential HCM and aging-associated molecular events mediate the late onset of HCM among MYBPC3 gene carriers. (A) Differential expression and enrichment of trans-acting factors in MYBPC3 cis-elements regulate MYBPC3 transcription upon aging. (B) Age-associated altered splicing mechanisms result in aberrant splice products, and (C) dysregulated mRNA degradation through nonsense-mediated pathways determines the abundance of MYBPC3 mRNA available for translation. (D) Aging-induced differences in the expression of miRNAs might modulate MYBPC3 translation through post-transcriptional gene silencing. (E) Age-dependent changes in phosphorylation, (F) ubiquitination proteasome system, (G) and chaperone-mediated autophagy determine the sufficiency of MYBPC3 protein in preserving cardiac function (Figure Created with BioRender.com).
Hypertrophic cardiomyopathy in MYBPC3 carriers in aging

January 2024

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180 Reads

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2 Citations

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3 ) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3 , underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.


Long-term efficacy and safety of cardiac genome editing for catecholaminergic polymorphic ventricular tachycardia

January 2024

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55 Reads

Introduction: Heterozygous autosomal-dominant single nucleotide variants in RYR2 account for 60% of cases of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia disorder associated with high mortality rates. CRISPR/Cas9-mediated genome editing is a promising therapeutic approach that can permanently cure the disease by removing the mutant RYR2 allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model. Aim: The purpose of this study was to assess whether adeno-associated virus type-9 (AAV9)-mediated somatic genome editing could prevent ventricular arrhythmias by removal of the mutant allele in mice that are heterozygous for Ryr2 variant p.Arg176Gln (R176Q/+). Methods and Results: Guide RNA and SaCas9 were delivered using AAV9 vectors injected subcutaneously in 10-day -old mice. At 6 weeks after injection, R176Q/+ mice had a 100% reduction in ventricular arrhythmias compared to controls. When aged to 12 months, injected R176Q/+ mice maintained a 100% reduction in arrhythmia induction. Deep RNA sequencing revealed the formation of insertions/deletions at the target site with minimal off-target editing on the wild-type allele. Consequently, CRISPR/SaCas9 editing resulted in a 45% reduction of total Ryr2 mRNA and a 38% reduction in RyR2 protein. Genome editing was well tolerated based on serial echocardiography, revealing unaltered cardiac function and structure up to 12 months after AAV9 injection. Conclusion: Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant Ryr2 allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT.




Adipose tissue lymphocytes and obesity

January 2024

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23 Reads

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3 Citations

Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.


Molecular mechanisms linking heart failure (HF) and sarcopenia. HF patients have reduced exercise tolerance, malnutrition, and altered hormonal signaling, including changes to aldosterone, angiotensin, cortisol, and catecholamine levels, all of which are linked to muscle wasting. Both HF and sarcopenia are associated with mitochondrial changes, including loss of maximal energy production and altered fuel utilization, increased oxidative stress, changes to mitochondrial fission/fusion leading to structural abnormalities, mitochondrial DNA (mtDNA) damage, and reduced mitochondrial protein quality control. Both HF and sarcopenia also have altered protein production and turnover, most notably involving autophagy and the ubiquitin-protease system (UPS), leading to proteostatic stress. Finally, HF is associated with chronic inflammation, particularly as evidenced by increased cytokine signaling involving TNF-α, IL-1, and IL-6, leading to muscle loss.
Overview of activity-related, nutritional, and hormonal changes in heart failure (HF) leading to muscle loss. HF patients have exercise intolerance and reduced mobility, leading to reduced exercise capacity. Some HF patients have reduced appetite or digestive issues in the gastrointestinal (GI) tract, leading to malnutrition and reduced protein intake, limiting the ability to sustain muscle growth. HF is also associated with increased renin-angiotensin-aldosterone system (RAAS) signaling, which promotes muscle loss over time. Finally, hormonal changes seen in HF, including growth hormone, catecholamine, ghrelin, and testosterone signaling, all drive an imbalance in catabolism over anabolism, resulting in muscle loss.
Changes to mitochondrial activity, behavior, and function common to failing myocardium and muscle tissue in sarcopenia. Mitochondria carry out a wide breadth of essential functions in the heart and muscle, and nearly all of these functions are dysregulated in heart failure and sarcopenia. Changes along the electron transport chain (Complexes I-IV and ATP synthase) lead to reduced ATP generation and increase superoxide release. Fuel utilization shifts from predominately fatty acids to alternative fuels, including glucose. Mitochondrial DNAs (mtDNAs) are damaged and released, leading to reduced mitochondrial biogenesis and activation of the innate immune response. Similarly, mitochondrial damage-associated molecular patterns (DAMPs) are exposed, triggering an immune response. Mitochondrial dynamics, including fission and fusion of established mitochondria, are altered, and reduced protein quality control can cause proteostatic stress in the cell.
Overview of molecular regulators of proteostasis. Maintenance of the proteome, including synthesis of new proteins and degradation of old and damaged proteins, is dysregulated in both the failing heart and sarcopenic muscle. Signal transducers linking hormonal and nutritional changes to protein synthesis are conserved between the heart and peripheral muscle, including mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3K) / protein kinase B (AKT), AMP-activated protein kinase, and mammalian target of rapamycin (mTOR). Signals promoting proteolysis include Forkhead box O (FoxO) proteins, which can promote transcription of F-box protein 32 (FBXO32) to increase expression of Atrogin-1 to activate the ubiquitin protease system (UPS). Similarly, activation of nuclear factor κB (NF-κB) triggers transcription of TRIM63 to drive Muscle RING-finger protein-1 (MuRF-1) expression and promote UPS. Kruppel-like factors (KLFs) are promoted by inactivity to inhibit protein synthesis.
Overview of cytokine changes in myocardium and skeletal muscle during Heart Failure (HF). HF can drive a wide breadth of inflammatory changes. Some of these include elevated pro-inflammatory hormonal signaling, gut edema allowing bacterial translocation, and exposure of damage-associate molecular patterns (DAMPs), leading to the release of cytokines including tumor necrosis factor (TNF) and interleukins (IL) 1 and 6. TNF can cause apoptosis, elevated reactive oxygen species (ROS), and mitochondrial DNA (mtDNA) damage in the musculature, leading to muscle damage and degradation. Transcription factors, including the Forkhead box O (FOXO) nuclear factor κB (NF-κB) families, are activated by cytokines, leading to altered proteostasis and activation of the ubiquitin-protease system (UPS).
Molecular mechanisms underlying sarcopenia in heart failure

January 2024

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119 Reads

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1 Citation

The loss of skeletal muscle, also known as sarcopenia, is an aging-associated muscle disorder that is disproportionately present in heart failure (HF) patients. HF patients with sarcopenia have poor outcomes compared to the overall HF patient population. The prevalence of sarcopenia in HF is only expected to grow as the global population ages, and novel treatment strategies are needed to improve outcomes in this cohort. Multiple mechanistic pathways have emerged that may explain the increased prevalence of sarcopenia in the HF population, and a better understanding of these pathways may lead to the development of therapies to prevent muscle loss. This review article aims to explore the molecular mechanisms linking sarcopenia and HF, and to discuss treatment strategies aimed at addressing such molecular signals.



Pre-treatment 18-FDG-PET-CT: (A) 18-FDG-PET-CT coronal view ventral slice: Prior to treatment of sarcoidosis. Visible hypermetabolic activity in the heart, lymph nodes, lungs, and bones (sacrum and thoracic spine). (B) 18-FDG-PET-CT sagittal view: Visible hypermetabolic activity in the heart and lungs.
Post-CPI-treatment 18-FDG-PET-CT: (A) 18-FDG-PET-CT coronal view ventral slice: full suppression of hypermetabolic activity in the heart, lungs, and lymph nodes indicating remission of the disease. (B) 18-FDG-PET-CT sagittal view: in comparison to PET-CT prior to sarcoidosis treatment, no potential CPI associated reactivation is visible, displaying regression of prior hypermetabolic activity.
A burning heart: combined therapy of checkpoint-inhibitors and prednisolone in a patient with sarcoidosis

January 2024

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30 Reads

Patients with prior autoimmune disease such as sarcoidosis require special care when treated with checkpoint inhibitors (CPIs), given the risk for reactivation of inflammation[1]. Here, we address the clinical dilemma of initiating CPIs for recurrent metastatic carcinoma in a patient with wide-spread sarcoidosis, controlled after prolonged immunosuppressive therapy when the tumor recurrence was detected. To achieve the best possible outcome, the case was discussed in an interdisciplinary team with specialists in rheumatology, oncology, and CPI related myocarditis. Literature on this topic was very limited. Based on the pharmacodynamics of CPIs and the pathophysiology of CPI related autoimmune diseases, we concluded that initiating CPIs under low dose prednisolone would provide sufficient suppression of any reactivation of sarcoidosis, while not interfering in a relevant way with CPIs.


Representation of the risk factors that contribute to the expansion of CH mutant clones. The identified risk factors encompass a range of conditions and exposures, including aging, chemotherapy and radiation treatments, inflammatory processes, germline variants, and lifestyle factors such as smoking, body mass index, diet, and diabetes. The presence of these CH clones has been associated with substantial health risks, including the development of multiple age-associated diseases, including cardiovascular disease and hematological malignancies, and with increased all-cause mortality. The graphical representation of these risk factors has been generated using BioRender.com.
Regulators of clonal hematopoiesis and physiological consequences of this condition

January 2024

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48 Reads

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1 Citation

Clonal hematopoiesis (CH) is a prevalent condition that results from somatic mutations in hematopoietic stem cells. When these mutations occur in “driver” genes, they can potentially confer fitness advantages to the affected cells, leading to a clonal expansion. While most clonal expansions of mutant cells are generally considered to be asymptomatic since they do not impact overall blood cell numbers, CH carriers face long-term risks of all-cause mortality and age-associated diseases, including cardiovascular disease and hematological malignancies. While considerable research has focused on understanding the association between CH and these diseases, less attention has been given to exploring the regulatory factors that contribute to the expansion of the driver gene clone. This review focuses on the association between environmental stressors and inherited genetic risk factors in the context of CH development. A better understanding of how these stressors impact CH development will facilitate mechanistic studies and potentially lead to new therapeutic avenues to treat individuals with this condition.



Distinct structure and expression patterns of GDF8 and GDF11. GDF8 and GDF11 share 89% amino acid identity in their mature domain, but only 52% in their prodomain. During processing, the signal sequence (SS) is removed, and the pre-pro-ligands are cleaved by Furin and Tolloid proteases (TLDs) to prepare the mature ligand for future signaling. GDF8, expressed predominantly in skeletal muscle, is cleaved by all TLDs and preferentially by TLL2 due to the availability of this TLD in the muscle, while the ubiquitously expressed GDF11 is cleaved preferentially by BMP1 and TLL1[6]. Figure made by @Biorender.
Proteolytic processing of GDF8 and GDF11 prodomains is a critical regulatory step. Proteolytic processing is necessary to pass from an unprocessed pre-pro complex protein to an active ligand able to signal. After a signal peptidase, the Furin protein recognizes and cleaves a specific motif -RXXR- between the prodomain and the mature domain. The inactive latent complex is then cleaved by the Tolloids family of protease to separate the prodomain from the active ligand. After cleavage, the prodomain is readily displaced when the mature ligand binds to the type II receptor and is likely degraded. Upon binding the type II receptor, a type I receptor is recruited and phosphorylated to activate downstream signaling pathways. The mature domain can also interact with inhibitors such as WFIKKN1, WFIKKN2, Follistatin (FS), or FSTL3.
Different potential states of GDF11. (i) Latent, with green and purple dimer and brown prodomains; (ii) Triggered as realized through acid activation; (iii) Tolloid processed; (iv) free ligand; and (v) antagonist bound with red and pink antagonists. + denotes active signaling states. Arrows indicate the possibility that some specific forms may change with age.
Human genetic diseases associated with GDF11 mutations. (A) 7 mutation sites have been identified in the GDF11 gene associated with several defects such as cleft palate and skeletal abnormalities. Mutations 1 and 2 are located in the prodomain, Mutations 3 and 4 in the Furin cleavage site, and Mutations 5-7 in the mature domain of GDF11. (B) Summary table of GDF11 mutations identified in humans. (+) indicates defects; (-) indicates no defect. + Ribs suggest skeleton defects. (C) Schematic depicting the functional impact of mutation 3, located in the Furin cleavage site, highlighting the importance of Furin cleavage for GDF11 activity.
GDF11 and aging biology - controversies resolved and pending

October 2023

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247 Reads

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1 Citation

Since the exogenous administration of GDF11, a TGF-ß superfamily member, was reported to have beneficial effects in some models of human disease, there have been many research studies in GDF11 biology. However, many studies have now confirmed that exogenous administration of GDF11 can improve physiology in disease models, including cardiac fibrosis, experimental stroke, and disordered metabolism. GDF11 is similar to GDF8 (also called Myostatin), differing only by 11 amino acids in their mature signaling domains. These two proteins are now known to be biochemically different both in vitro and in vivo . GDF11 is much more potent than GDF8 and induces more strongly SMAD2 phosphorylation in the myocardium compared to GDF8. GDF8 and GDF11 prodomain are only 52% identical and are cleaved by different Tolloid proteases to liberate the mature signaling domain from inhibition of the prodomain. Here, we review the state of GDF11 biology, highlighting both resolved and remaining controversies.


Polymerase gamma mutation drives altered mitochondrial gene expression in the cardiac right ventricle. Experimental workflow is depicted (A). Row normalized expression of the 37 mitochondria encoded genes is shown in heatmap format (B). Twelve of the 22 mt-tRNAs showed altered expression in the POL mutant (C).
Chromosomal location-specific effect of POLG mutation on mt-tRNA expression as measured by RNA-Seq. Expression of clustered mt-tRNAs in WT and POLG mutant mice is presented in relation to location of encoding within the mitochondrial genome. A pattern of 4 local clusters of mt-tRNAs emerges where each mt-tRNA in the cluster shows similar changes in gene expression in response to POLG mutation (center depiction of mitochondrial chromosome derived in BioRender).
POLG-dependent changes in mitochondrial gene expression are not associated with promoter usage. Genes are depicted based on expression from mitochondrial promoters HSP (A) and LSP (B). Descriptor column provides information related to gene function. Log2FC in POLG mutant relative to control RV tissue show opposite direction of gene expression regulation from the same promoterr.
POLG-dependent changes in mt-tRNAs are negatively correlated with amino acid amyloidogenic potential. Log2FC values for significantly altered mt-tRNAs in the POLG mutant (X-axis) were plotted against a series of amino acid characteristic scores (Y-axis) used for predicting amino acid contributions to protein aggregation and beta-amyloid formation (A-D). Linear regression analysis confirms significant negative correlation with FoldAM triple hybrid and regular scoring criteria (A and B). There was a positive correlation with the AA's sum contact potential value (C) and side chain orientation scores (D). These scores can be indicative of the AA's propensity to mediate specific protein:protein interactions. As another validation, group analysis (t-test) confirmed lower FoldAM triple hybrid score for mt-tRNAs that showed significantly increased vs. decreased expression in the POLG mutant (E).
Northern blot analysis of candidate mt-tRNAs identified from RNA-seq analysis. Three mt-tRNAs were selected for measurement by northern blot in cardiac RV and LV tissue: (1)MT-TL1 (control, no change in RNA seq); (2) MT-TY (significantly decreased in RNA-seq); and (3) MT-TP (significantly increased in RNA-seq). In the RV, MT-TY showed significantly reduced abundance in the POLG mutant relative to WT controls (confirming RNA-seq finding) while MT-TP showed no change in abundance between the groups [Northern blots shown in (A) and quantified in (B)]. This pattern of mt-tRNA abundance between WT and POLG mutants was also present in the LV tissue (C and D).
mt-tRNAs in the polymerase gamma mutant heart

October 2023

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30 Reads

Introduction: Mice harboring a D257A mutation in the proofreading domain of the mitochondrial DNA polymerase, Polymerase Gamma (POLG), experience severe metabolic dysfunction and display hallmarks of accelerated aging. We previously reported a mitochondrial unfolded protein response (UPTmt) - like (UPRmt-like) gene and protein expression pattern in the right ventricular tissue of POLG mutant mice. Aim: We sought to determine if POLG mutation altered the expression of genes encoded by the mitochondria in a way that might also reduce proteotoxic stress. Methods and Results: The expression of genes encoded by the mitochondrial DNA was interrogated via RNA-seq and northern blot analysis. A striking, location-dependent effect was seen in the expression of mitochondrial-encoded tRNAs in the POLG mutant as assayed by RNA-seq. These expression changes were negatively correlated with the tRNA partner amino acid’s amyloidogenic potential. Direct measurement by northern blot was conducted on candidate mt-tRNAs identified from the RNA-seq. This analysis confirmed reduced expression of MT-TY in the POLG mutant but failed to show increased expression of MT-TP, which was dramatically increased in the RNA-seq data. Conclusion: We conclude that reduced expression of amyloid-associated mt-tRNAs is another indication of adaptive response to severe mitochondrial dysfunction in the POLG mutant. Incongruence between RNA-seq and northern blot measurement of MT-TP expression points towards the existence of mt-tRNA post-transcriptional modification regulation in the POLG mutant that alters either polyA capture or cDNA synthesis in RNA-seq library generation. Together, these data suggest that 1) evolution has distributed mt-tRNAs across the circular mitochondrial genome to allow chromosomal location-dependent mt-tRNA regulation (either by expression or PTM) and 2) this regulation is cognizant of the tRNA partner amino acid’s amyloidogenic properties.


Retinoic acid-related orphan receptors regulate autophagy and cell survival in cardiac myocytes during hypoxic stress

October 2023

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67 Reads

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4 Citations

Introduction: Autophagy is a highly conserved evolutionary process that regulates cell quality control through protein degradation, organelle turnover, and recycling of cellular components by fusing with lysosomes. Defects in autophagy can lead to increased reactive oxygen species (ROS) and oxidative stress from impaired mitochondrial clearance by mitophagy. These defects are commonly associated with chronic human diseases such as cancer, myocardial infarction, neurodegenerative diseases, and aging. Aim: Herein, we show that the gene Retinoic Acid-Related Orphan Receptors α (Rora) is cardioprotective through modulation of autophagy and clearance of damaged ROS-producing mitochondria in cardiac myocytes. Methods and results: We show that RORα is downregulated during hypoxia, leading to increased death of cardiac cells and enhanced mitochondrial perturbations. We demonstrate that the small molecule Nobiletin, a polymethoxy flavonoid, can induce RORα activation and downregulate the aging-associated marker p16, coincident with reduced ROS-producing mitochondria. We further show that Nobiletin binds directly to the Rora gene promoter, leading to activation of autophagic function and increased cell survival of cardiac myocytes during hypoxia. Interestingly, loss of RORα activity during hypoxia resulted in the failure of Nobiletin to rescue autophagy and inhibits its capacity for cardiac protection. Furthermore, the inactivation of autophagy by ATG7 knockdown abrogated the cytoprotective effects of Nobiletin on autophagic activation. Conclusion: Collectively, these results demonstrate that RORα regulates autophagic processes linked to aging upon activation with Nobiletin. Interventions that activate RORα may prove beneficial in reducing hypoxia-induced mitochondrial ROS associated with cardiac aging.


Temporal distribution of increased INR reports to the FAERS database.
Geographical distribution of increased INR reports (case number > = 20) to the FAERS database.
Association between INR increase and other ADRs in patients prescribed Warfarin
Age difference in the risk of increased international normalized ratio
Association rules to identify which compounds may interact with warfarin
The association between warfarin usage and international normalized ratio increase: systematic analysis of FDA Adverse Event Reporting System (FAERS)

October 2023

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51 Reads

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2 Citations

Introduction: Elevated international normalized ratio (INR) has been commonly reported as an adverse drug event (ADE) for patients taking warfarin for anticoagulant therapy. Aim: The purpose of this study was to determine the association between increased INR and the usage of warfarin by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS). Methods: The ADEs in patients who took warfarin (N = 77,010) were analyzed using FAERS data. Association rule mining was applied to identify warfarin-related ADEs that were most associated with elevated INR (n = 15,091) as well as possible drug-drug interactions (DDIs) associated with increased INR. Lift values were used to identify ADEs that were most commonly reported alongside elevated INR based on the correlation between both item sets. In addition, this study sought to determine if the increased INR risk was influenced by sex, age, temporal distribution, and geographic distribution and were reported as reporting odds ratios (RORs). Results: The top 5 ADEs most associated with increased INR in patients taking warfarin were decreased hemoglobin (lift = 2.31), drug interactions (lift = 1.88), hematuria (lift = 1.58), asthenia (lift = 1.44), and fall (lift = 1.32). INR risk increased as age increased, with individuals older than 80 having a 63% greater likelihood of elevated INR compared to those younger than 50. Males were 9% more likely to report increased INR as an ADE compared to females. Individuals taking warfarin concomitantly with at least one other drug were 43% more likely to report increased INR. The top 5 most frequently identified DDIs in patients taking warfarin and presenting with elevated INR were acetaminophen (lift = 1.81), ramipril (lift = 1.71), furosemide (lift = 1.64), bisoprolol (lift = 1.58), and simvastatin (lift = 1.58). Conclusion: The risk of elevated INR increased as patient age increased, particularly among those older than 80. Elevated INR frequently co-presented with decreased hemoglobin, drug interactions, hematuria, asthenia, and fall in patients taking warfarin. This effect may be less pronounced in women due to the procoagulatory effects of estrogen signaling. Multiple possible DDIs were identified, including acetaminophen, ramipril, and furosemide.



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