D. Brian Foster

Johns Hopkins Medicine | JHUSOM · Division of Cardiology

Ca(2+) control of troponin-tropomyosin position on actin regulates cardiac muscle contraction. The inhibitory subunit of troponin, cardiac troponin (cTn)I is primarily responsible for maintaining a tropomyosin conformation that prevents crossbridge cycling. Despite extensive characterization of cTnI, the precise role of its C-terminal domain (resid...

Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mec...

In the heart, lysine acetylation has been implicated in processes ranging from transcriptional control of pathological remodeling, to cardioprotection arising from caloric restriction. Given the emerging importance of this post-translational modification, we used a proteomic approach to investigate the broader role of lysine acetylation in the hear...

Heart failure (HF) is a complex condition characterized by the inability of the heart to pump sufficient oxygen to the organs to meet their metabolic needs. Among the altered signal transduction pathways associated with HF pathogenesis, the p38 mitogen-activated protein kinase (p38 MAPK) pathway—activated in response to stress— has attracted consid...

Background Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19. Methods Radiotelemetry in conscious animals...

BACKGROUND A healthy heart is able to modify its function and increase relaxation through posttranslational modifications of myofilament proteins. While there are known examples of serine/threonine kinases directly phosphorylating myofilament proteins to modify heart function, the roles of tyrosine (Y) phosphorylation to directly modify heart funct...

Background: Ca ²⁺ /calmodulin-dependent protein kinase II (CaMKII) is an established negative regulator of cardiac injury. Both the expression and activity levels of CaMKII delta, the primary cardiac isoform of this kinase, are elevated in models of heart failure (HF) such as ischemia-reperfusion (I/R) injury and following myocardial infarction (MI...

The regulated and reversible modification of Ser/Thr residues by O-linked N-Acetylglucosamine (O-GlcNAc) is termed O-GlcNAcylation. O-GlcNAc cycling on and off proteins is regulated by two conserved enzymes, the ‘writer’ O-GlcNAc Transferase (OGT) and the ‘eraser’ O-GlcNAcase (OGA). Crucially, O-GlcNAcylation is implicated in nutrient sensing, cell...

Intro: Cardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome, but the mechanisms behind COVID-19-linked arrhythmias are unknown. Here, we test the hypothesis that innate immune activation and mitochondrial ROS contribute to cardiac conduction abnormalities and pulmonary dysfunction in a COVID-19 hamster model. Results: ECG...

Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated CI markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear....

The dynamic cycling of O-linked N-Acetylglucosamine (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAc cycling is important in homeostatic and stress responses and its perturbation sensitizes the heart to ischemic a...

Angiotensin system, aging, and Alzheimer's disease are tightly linked. Of the brain angiotensin receptors, the subtype 2 receptor (AT2R) is relatively less studied. Canonically, the AT2R functions through nitric oxide release, and its activation has been linked to vasodilatation and neurite outgrowth as well as anti-inflammation. How AT2R signals i...

Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac ov...

Background: The COVID-19 pandemic has highlighted how little is known about how double stranded RNA (dsRNA) viruses like the SARS-CoV-2 impact cardiac physiology acutely and long-term. While it is unclear if the cardiac effects are direct or indirect, adverse effects in patients are common, including cardiac inflammation, electrophysiological chang...

Previously, we reported that heterologous expression of an embryonic transcription factor, Tbx18, reprograms ventricular cardiomyocytes into induced pacemaker cells (Tbx18-iPMs), though the key pathways are unknown. Here, we have used a tandem mass tag proteomic approach to characterize the impact of Tbx18 on neonatal rat ventricular myocytes. Tbx1...

The cytokine interleukin-6 (IL-6) has pleiotropic effects in aging and is elevated in frail older adults. We have developed a conditional mouse model to better characterize the role of IL-6 in promoting frailty and age-related mitochondrial dysregulation. The human IL-6 (hIL-6) knock-in mouse (TetO-hIL6) was developed utilizing CRISPR/Cas9 technolo...

Chronic wounds are a common and debilitating condition associated with aging populations that impact more than 6.5 million patients in the United States. We have previously demonstrated the efficacy of daily topical 1% valsartan in treating wounds in diabetic mouse and pig models. Despite these promising results, there remains a need to develop an...

The mitogen activated protein kinase (MAPK) p38 is important in cardiac hypertrophic responses and p38 inhibition has been tested as a potential therapeutic approach to heart failure. p38 is tightly regulated by upstream kinases and phosphatases. While p38 inhibitors suppress cardiac hypertrophy in vitro and in animal models, the partial efficacy o...

Though low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we show that proteomic analyses of human and guinea pig heart failure (HF)...

Altered Serine/Threonine phosphorylation of the cardiac proteome is an established hallmark of heart failure (HF). However, the contribution of tyrosine phosphorylation to the pathogenesis of these diseases remains unclear. The cardiac proteome was explored by global mapping to discover and quantify site-specific tyrosine phosphorylation in two car...

Recent proteomics studies of vertebrate striated muscle have identified lysine acetylation at several sites on actin. Acetylation is a reversible post-translational modification (PTM) that neutralizes lysine’s positive charge. Actin’s positively charged residues, particularly K326 and K328, are predicted to form several, critical electrostatic inte...

Utilizing a Drosophila model of inclusion body myopathy 3 (IBM‐3), we identified a subset of stress‐response proteins essential for skeletal muscle proteostasis in both health and disease. Inclusion body myopathy 3 (IBM‐3) is a rare, dominant skeletal muscle disease caused by an E706K substitution in the SH1 helix of myosin heavy chain IIa. We prod...

The renal-outer-medullary‑potassium (ROMK) channel, mutated in Bartter's syndrome, regulates ion exchange in kidney, but its extra-renal functions remain unknown. Additionally, ROMK was postulated to be the pore-forming subunit of the mitochondrial ATP-sensitive K+ channel (mitoKATP), a mediator of cardioprotection. Using global and cardiomyocyte-s...

Objective: Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acet...

The heart’s pacemaker cells contain mitochondria that are smaller than average and require less energy than other heart cells, properties that help make them naturally resilient to stress. Cardiac pacemaker cells constitute a tiny proportion of the heart’s cells, yet play a critical role in maintaining a steady heartbeat. However, quite how pacemak...

Objective: Cardiac troponin I (cTnI) is an essential regulator of cardiac contractility and relaxation. Mutations within key regions of this regulator lead to cardiomyopathies. Further, post-translational modification of cTnI through phosphorylation impacts myofibril relaxation and calcium sensitivity. Recent studies have also demonstrated that myo...

Pathway analyses of proteomic studies in guinea pig and rat hearts subjected to pressure overload-induced hypertrophy and heart failure (HF) suggest aberrant retinoid signaling may contribute to HF progression. Though the precise mechanisms are unknown, we recently showed that cardiac levels of the hormone all-trans retinoic acid (ATRA) are deficie...

Rationale: Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how RO...

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnos...

Adult stem cells demonstrate metabolic flexibility that is regulated by cell adhesion status. The authors demonstrate that adherent cells primarily utilize glycolysis, whereas suspended cells rely on oxidative phosphorylation for their ATP needs. Akt phosphorylation transduces adhesion-mediated regulation of energy metabolism, by regulating translo...

Introduction: Recently, we have investigated a pressure-overload/chronic catecholamine guinea pig model (ACi) of cardiac hypertrophy (HYP) and HF with the unique features of acquired long QT syndrome and sudden cardiac death (SCD) by quantitative global-scale proteomics using isobaric tags for relative and absolute quantitation. Hypothesis: By comp...

Although tens, or even hundreds, of molecular or pharmacological interventions have been shown to affect the course of heart failure in animal models, few have translated to clinical therapies. This likely stems from the fact that biological robustness and flexibility are conferred by the evolution of redundant or adaptive signaling and gene expres...

Proteomics experiments are as diverse as the scientists who perform them. Goals range from the desire to understand a subcellular structure or an individual protein in greater depth, to identification of novel protein-protein interactions. Or perhaps, the goal is to obtain a global protein abundance profile from an animal model of cardiovascular di...

The analysis of post-translational modifications is critical for understanding the regulation of protein function in the heart. These small, often charged, groups are added to a protein’s structure to modulate its activity, localization or associations. The development of proteomic technologies has greatly improved the identification and subsequent...

Whether you are a proteomics specialist or simply an end-user of proteomic data, the day will come when you sit down with your dataset, typically a list of proteins or protein clusters whose abundance change in one or more experimental groups. This protein change is often represented as a ratio or fold-change. When the euphoria wears off, the naggi...

This book highlights the remarkable advances that have contributed to the development of proteomics over the last two decades. While many of the concepts, methods, and technologies can be widely applied across fields of biomedical research, this book has been tailored for the cardiovascular researcher, with the many facets of cardiovascular disease...

Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective...

In striated muscle tropomyosin (Tm) extends along the length of F-actin-containing thin filaments. Its location governs access of myosin binding sites on actin and, hence, force production. Intermolecular electrostatic associations are believed to mediate critical interactions between the proteins. For example, actin residues K326, K328, and R147 w...

This forum addresses the role of mitochondrial dysfunction in the multifactorial nature of diabetic cardiomyopathy from multiple angles. Contributors deliver a diverse and in-depth view of the state-of-the-art in diabetic cardiomyopathy, from bench to bedside. What emerges is a picture of mitochondrial dysfunction as a central, upstream defect, inf...

Phosphorylation of cardiac troponin I (cTnI) by protein kinase C (PKC) is implicated in cardiac dysfunction. Recently, Serine 199 (Ser199) was identified as a target for PKC phosphorylation and increased Ser199 phosphorylation occurs in end-stage failing compared with non-failing human myocardium. The functional consequences of cTnI-Ser199 phosphor...

Striated muscle contraction is driven by cyclical interaction between myosin-containing thick and actin-containing thin filaments and is regulated by the tropomyosin-troponin complex. In the absence of calcium, troponin constrains tropomyosin in a blocking position where it shields myosin binding sites on actin. Calcium binding to troponin enables...

Background: Mitochondria produce reactive oxygen species (ROS) that are scavenged by local antioxidant enzymes. Glutathione (GSH) is key intermediate in many of these reactions and its availability determines the antioxidant capacity of mitochondria. Glutathione S-transferases (GSTs) are known to consume GSH during xenobiotic detoxification but the...

Mechanistic understanding of heart failure (HF) and sudden cardiac death (SCD) has been hampered by the lack of suitable experimental models with features of human disease. We have developed a guinea pig model of cardiac hypertrophy (HYP) and HF, characterized by predisposition to SCD (Liu et al. Circ. Res. 2014). Our objective was to refine guinea...

Inclusion body myopathy type 3 (IBM-3) is a progressive dominant disease affecting fast skeletal muscle. It results from a point mutation in the SH1 helix of the myosin motor. Previously, we showed that homozygous expression of the analogous mutation in Drosophila indirect flight muscle (IFM) results in a flightless phenotype, severe abnormalities...

Aims: Troponin I variant Pro82Ser (cTnIP82S) was initially considered a disease-causing mutation, however, later studies suggested the contrary. We tested the hypothesis of whether a causal link exists between cTnIP82S and cardiac structural and functional remodeling, such as during aging or chronic pressure-overload. Methods and results: A cardiac...

Lysine modifications have been studied extensively in the nucleus, where they play pivotal roles in gene regulation and constitute one of the pillars of epigenetics. In the cytoplasm, they are critical to proteostasis. However, in the last decade we have also witnessed the emergence of mitochondria as a prime locus for post-translational modificati...

Protein kinase C (PKC)-mediated phosphorylation of troponin I (cTnI) at Ser42/44 is increased in heart failure. While studies in rodents demonstrated that PKC-mediated Ser42/44 phosphorylation decreases maximal force and ATPase activity, PKC incubation of human cardiomyocytes did not affect maximal force. We investigated whether Ser42/44 pseudo-pho...

Here we explored the impact of hydrogen sulfide (H2S) on biophysical properties of the primary human airway smooth muscle (ASM)-the end effector of acute airway narrowing in asthma. Using Magnetic Twisting Cytometry (MTC), we measured dynamic changes in the stiffness of isolated ASM, at the single-cell level, in response to varying doses of GYY4137...

Frank-Starling's law reflects the ability of the heart to adjust the force of its contraction to changes in ventricular filling, a property based on length-dependent myofilament activation (LDA). The threonine at amino acid 143 of cardiac troponin I (cTnI) is prerequisite for the length-dependent increase in Ca(2+)-sensitivity. Thr143 is a known ta...

We have recently reported that mitoROMK overexpression protects against, while knockdown of native ROMK exacerbates, oxidative stress-induced cell death and have proposed mitoROMK as the molecular correlate of the cardioprotective mitoKATP channel (Foster, Ho, et al Circ Res 2012). In order to better understand the mechanisms of protection, here we...

BINGO Analysis. Sheet 1: Gene set enrichment of ontologies related to biological processes. Sheet 2: Gene set enrichment of ontologies related to molecular function. Sheet 3: Gene set enrichment of ontologies related to cellular components. These Tables include only terms deemed statistically significant (p<0.01) after Benjamini-Hochberg correction...

PTM Count & Site Probability, Spectrum Report, Peptide Report. Sheet 1 shows the sites of acetylation, the statistical probability that the acetyl group can be assigned to a specific lysine residue (in lower case k), and the the number of times that a site was identified in each of 24 LC-MS/MS runs. Sheet 2 provides spectrum data obtained for all a...

Acetyl-proteins & Sites. Sheet 1: Additional annotation is provided for Figure 3 in the manuscript, including the numbering of orthologous lysines in human sequences. A simplified gene ontology annotation (GO SLIM) is also provided as well as the distribution of identified peptides across biological samples and subcellular fractions. Sheet 2 provid...

Intraprotein Site Identification Frequency. For each acetylation site identified, the number of spectra implicating that site is expressed as a percentage of the total number of spectra attributed to all acetylation sites within a given protein. This provides an indication of the relative frequency with which each site on a protein was identified....

Rationale: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. Objective...

Protein kinase A (PKA)-mediated phosphorylation of contractile proteins upon β-adrenergic stimulation plays an important role in regulation of cardiac performance. Phosphorylation of the PKA sites (Ser23/Ser24) of cardiac troponin I (cTnI) results in a decrease in myofilament Ca(2+)-sensitivity and an increase in the rate of relaxation. However, th...

Rationale: In the myocardium, redox/cysteine modification of proteins regulating Ca(2+) cycling can affect contraction and may have therapeutic value. Nitroxyl (HNO), the one-electron-reduced form of nitric oxide, enhances cardiac function in a manner that suggests reversible cysteine modifications of the contractile machinery. Objective: To det...

Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown. Objective: To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP). Mass s...

As we learn more about the factors that govern cardiac mitochondrial bioenergetics, fission and fusion, as well as the triggers of apoptotic and necrotic cell death, there is growing appreciation that these dynamic processes are finely-tuned by equally dynamic post-translational modification of proteins in and around the mitochondrion. In this mini...

ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buff...