Stephen L Archer's research while affiliated with Queen's University and other places

Publications (438)

Article
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Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH. Methods: In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectromet...
Article
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Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV-macrophages to PAH-RVF. Methods: Rats with decompensated RV hypertrophy (RVH) [monocrotaline (MCT) and Sugen-54...
Preprint
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The novel coronavirus disease of 2019 (COVID-19) pandemic has severely impacted the training of health care professional students because of concerns of potential asymptomatic transmission to colleagues and vulnerable patients. From May 27th, 2020, to June 23rd 2021; at a time when B.1.1.7 (alpha) and B.1.617.2 (delta) were the dominant circulating...
Article
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Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitoch...
Article
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Real‐world identification of Pulmonary Hypertension (PH) is largely based on the use of administrative databases identified by ICD codes. This approach has not been validated. The aim of this study was to validate a diagnosis of PH and its comorbidities using ICD 9/10 codes. Health records from Kingston Health Sciences Centre (2010‐2012) were abstr...
Article
Introduction Group 2 pulmonary hypertension (PH) has no approved PH-targeted therapy. Metabolic remodeling, specifically a biventricular increase in pyruvate kinase muscle (PKM) isozyme 2 to 1 ratio, occurs in rats with Group 2 PH induced by supra-coronary aortic banding (SAB). We hypothesize that increased PKM2/PKM1 is maladaptive and inhibiting P...
Article
Background Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. G...
Article
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The Ductus Arteriosus (DA) is a fetal vessel that connects the aorta to the pulmonary artery ensuring that placental oxygenated blood is diverted from the lungs to the systemic circulation. Following exposure to oxygen (O2), in the first few days of life, the DA responds with a functional closure that is followed by anatomical closure. Here, we stu...
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Background Neutrophils play a role in innate immunity and are critical for clearance of Staphylococcus aureus. Current understanding of neutrophil bactericidal effects is that NADPH oxidase produces reactive oxygen species (ROS), mediating bacterial killing. Neutrophils also contain numerous mitochondria; since these organelles lack oxidative metab...
Article
BACKGROUND: Neutrophils, the most abundant leukocytes and granulocytes, are important regulators of cardiovascular, inflammatory and infectious diseases, yet their role in the pathophysiology of clonal hematopoiesis of indeterminate potential (CHIP) has not been adequately addressed. The effects of inactivating CHIP-driver mutations in the epigenet...
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Iron-sulfur (Fe–S) clusters are essential cofactors most commonly known for their role mediating electron transfer within the mitochondrial respiratory chain. The Fe–S cluster pathways that function within the respiratory complexes are highly conserved between bacteria and the mitochondria of eukaryotic cells. Within the electron transport chain, F...
Article
Impaired mitochondrial fusion, due in part to decreased mitofusin 2 (Mfn2) expression, contributes to unrestricted cell proliferation and apoptosis‐resistance in hyperproliferative diseases like pulmonary arterial hypertension (PAH) and non‐small cell lung cancer (NSCLC). We hypothesized that Mfn2 levels are reduced due to increased proteasomal deg...
Article
The ductus arteriosus (DA) connects the fetal pulmonary artery and aorta, diverting placentally oxygenated blood from the developing lungs to the systemic circulation. The DA constricts in response to increases in oxygen (O2) with the first breaths, resulting in functional DA closure, with anatomic closure occurring within the first days of life. F...
Article
Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Ins...
Article
The homeostatic oxygen sensing system (HOSS) optimizes systemic oxygen delivery. Specialized tissues utilize a conserved mitochondrial sensor, often involving NDUFS2 in complex I of the mitochondrial electron transport chain, as a site of pO2-responsive production of reactive oxygen species (ROS). These ROS are converted to a diffusible signaling m...
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Background The impact of pulmonary hypertension (PH) on outcomes after surgical tricuspid valve replacement (TVR) and repair (TVr) is unclear. We sought to characterize PH in patients undergoing TVR/TVr based on invasive hemodynamics and evaluate the effect of PH on mortality. Methods We identified 86 consecutive patients who underwent TVR/TVr wit...
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A 51-year old woman with pulmonary arterial hypertension (PAH) presented with progressive chest pain and dyspnea. Computed tomography demonstrated significant enlargement of her main pulmonary artery (PA) and was suggestive of left main coronary artery (LMCA) compression by the PA. The patient underwent percutaneous coronary intervention (PCI) whic...
Article
Introduction: Female sex is associated with better right ventricular (RV) function in pulmonary hypertension (PH). The female sex hormone 17-beta-estradiol is postulated to mediate these differences, but the molecular mechanisms underlying these observations are incompletely defined. Interestingly, 17-beta-estradiol induces microtubule depolymeriza...
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Objective Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppress...
Article
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The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-Gl...
Article
Background Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly un...
Article
Managing healthcare in the Coronavirus Disease 2019 (COVID-19) era should be guided by ethics, epidemiology, equity, and economics, not emotion. Ethical healthcare policies ensure equitable access to care for patients regardless of whether they have COVID-19 or another disease. Because healthcare resources are limited, a cost per Quality Life Year...
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Background Although detection of elevated right ventricular systolic pressure (RVSP) on routine echocardiography is common, its clinical significance is underappreciated. The recent change in the hemodynamic definition of pulmonary hypertension lowering the threshold from mean pulmonary arterial pressure (mPAP)≥25 mmHg to >20 mmHg further clouds th...
Article
Aim Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction due, in part, to RV ischemia. The relative contribution of RV microvascular rarefaction versus reduced right coronary artery perfusion pressure (RCA‐PP) to RV ischemia is unknown. We hypothesize that increasing RCA‐PP improves RV function in PAH by increasing RV...
Article
Rationale: Right ventricular (RV) fibrosis in pulmonary arterial hypertension (PAH) contributes to RV failure (RVF). While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied. Objective: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental PAH. Metho...
Article
Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation,...
Chapter
In lung vascular cells, mitochondria serve a canonical metabolic role, governing energy homeostasis. In addition, mitochondria exist in dynamic networks, which serve noncanonical functions, including regulation of redox signaling, cell cycle, apoptosis, and mitochondrial quality control. Mitochondria in pulmonary artery smooth muscle cells (PASMC)...
Article
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Background Pulmonary arterial hypertension ( PAH ) is a lethal disease. In resource‐limited countries PAH outcomes are worse because therapy costs are prohibitive. To improve global outcomes, noninvasive and widely available biomarkers that identify high‐risk patients should be defined. Serum chloride is widely available and predicts mortality in l...
Article
Excessive proliferation and apoptosis-resistance are hallmarks of cancer. Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is one of the mediators of this phenotype. Mitochondrial fission that accompanies the nuclear division is called mitotic fission and occurs when activated Drp1 binds partner proteins on the outer mitoch...
Article
Mitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes, such as the production of reactive oxygen species (ROS) during cardiac ischemia-reperfusion injury (IR). Mitochondrial fission is mainly mediated by dynamin-related protein 1 (Drp1), a...
Article
Objectives: Cardiogenic shock following cardiopulmonary resuscitation for sudden cardiac arrest is common, occurring even in the absence of acute coronary artery occlusion, and contributes to high rates of postcardiopulmonary resuscitation mortality. The pathophysiology of this shock is unclear, and effective therapies for improving clinical outco...
Article
While a majority of the mammalian genome is transcribed to RNA, mounting evidence indicates that only a minor proportion of these transcriptional products are actually translated into proteins. Since the discovery of the first non-coding RNA (ncRNA) in the 1980s, the field has gone on to recognize ncRNAs as important molecular regulators of RNA act...
Article
Background: Cardiogenic shock following cardiopulmonary resuscitation (CPR) for sudden cardiac arrest is common, occurring even in the absence of acute coronary artery occlusion, and contributes to high rates of post-CPR mortality. The pathophysiology of this shock is unclear and effective therapies for improving clinical outcomes are lacking. Meth...
Article
Rationale: Hypoxic pulmonary vasoconstriction (HPV) optimizes systemic oxygen delivery by matching ventilation to perfusion. HPV is intrinsic to pulmonary artery smooth muscle cells (PASMCs). Hypoxia dilates systemic arteries, including renal arteries. Hypoxia is sensed by changes in mitochondrial-derived reactive oxygen species, notably hydrogen...
Article
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Rationale: Pulmonary hypertension (PH) due to left heart disease (PH-LHD), or Group2-PH, is the most prevalent form of PH worldwide. PH-LHD is often associated with metabolic syndrome (MetS). In 12-13% of cases, patients with PH-LHD display vascular remodeling of pulmonary arteries associated with poor prognosis. Unfortunately, the underlying mech...
Article
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Arrhythmias are increasingly recognized as serious, end-stage complications of pre-capillary pulmonary hypertension, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Although arrhythmias contribute to symptoms, morbidity, in-hospital mortality, and possibly sudden death in PAH/CTEPH, there r...
Data
Pyruvate dehydrogenase (PDH) enzyme activity dipstick assay showing no significant change in the (A) left ventricle (LV) and the (B) right ventricle (RV) PDH enzyme activity.
Data
Heart rate and respiratory rate 4 weeks post banding surgery. (A) Representative electrocardiogram and respiratory trace of sham and supra-coronary aortic banding (SAB) rat. (B) Respiratory rate is significantly increased in SAB vs. sham rats. (C) Heart rate is not significantly increased in SAB vs. sham rats.
Data
Supra-coronary aortic banding surgery. (A) Incision made at 3rd intercostal space and held open with three surgical hooks; (B) the aorta was located; (C) the connective tissue between aorta and pulmonary artery was carefully removed with a pair of blunt tweezers; (D) a small metal clip was applied to the isolated aorta, constricting it by 50–60%; (...
Data
Western blot showing no significant change of phospho-pyruvate dehydrogenase (pPDH) to pyruvate dehydrogenase (PDH) ratio in the (A) left ventricle (LV) and (B) right ventricle (RV) of supra-coronary aortic banding (SAB) rats vs. sham rats. Each band represents a unique animal. Two experimental cohorts were done; hence two groups are shown, labeled...
Article
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Introduction: Group 2 pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure ≥25 mmHg with elevated pulmonary capillary wedge pressure >15 mmHg, has no approved therapy and patients often die from right ventricular failure (RVF). Alterations in mitochondrial metabolism, notably impaired glucose oxidation, and increased mitochond...
Data
Supra-coronary aortic banding (SAB) group 2 pulmonary hypertension rat model experimental design.
Data
Western blot showing no change in mitochondrial dynamics of 49 kDa protein (MiD49) in the (A) left ventricle (LV) and (B) right ventricle (RV) of supra-coronary aortic banding (SAB) rats vs. sham rats. Each band represents a unique animal. Two experimental cohorts were done; hence two groups are shown, labeled as 1 and 2. The same vinculin loading...
Article
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Background Patients with pulmonary hypertension caused by chronic lung disease (Group 3 PH) have disproportionate right ventricle (RV) dysfunction, but the correlates and clinical implications of RV dysfunction in Group 3 PH are not well defined. Methods and Results We performed a cohort study of 147 Group 3 PH patients evaluated at the University...
Article
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Pulmonary arterial hypertension (PAH) is a rare but lethal disorder caused by several pathological changes in the pulmonary vasculature. There is endothelial cell dysfunction characterized by exaggerated secretion of vasoconstrictive, pro-proliferative substances, such as endothelin, and impaired release of vasodilatory, antiproliferative molecules...
Article
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Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes...
Article
The mechanism of mitral stenosis-induced pulmonary venous arterialization and group 2 pulmonary hypertension (PH) is unclear. There is no rodent model of group 2 PH, due to mitral stenosis (MS), to facilitate the investigation of disease mechanisms and potential therapeutic strategies. We present a novel rat model of pulmonary venous congestion-ind...
Article
Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by remodelling of distal pulmonary arteries associated with inflammation, endothelial cells (EC) dysfunction and a pro-proliferative/anti-apoptotic phenotype in pulmonary arterial smooth muscle cells (PASMC). Tet methylcytosine dioxygenase 2 (Tet2) is a key enz...
Article
Mitochondrial metabolism relies on membrane potential (ΔΨm) for effective electron transport across respiratory complexes and a filamentous mitochondrial network. Oxidative metabolism is typically measured via bioenergetic assays utilizing electron transport chain inhibitors including oligomycin (ATP synthase inhibitor), FCCP (proton ionophore), an...
Article
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Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV),...
Article
Background: Patients with pulmonary hypertension (PH) due to chronic lung disease (Group 3 PH) have poor long-term outcomes. However, predictors of survival in Group 3 PH are not well described. Methods: We performed a cohort study of Group 3 PH patients (n = 143; mean age 65 ± 12 years, 52% female) evaluated at the University of Minnesota. The...
Article
Background: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart...
Article
Introduction: Right ventricular (RV) function is a critical predictor of both morbidity and mortality in pulmonary arterial hypertension (PAH). In PAH patients present either with adaptive remodelling RV and compensatory RV hypertrophy (RVH), or maladaptive remodeling that rapidly deteriorates to RV failure (RVF). While the molecular mechanisms und...
Article
Full-text available
Introduction: Right ventricular (RV) fibrosis contributes to RV failure in pulmonary arterial hypertension (PAH). The mechanisms underlying RV fibrosis in PAH and the role of RV fibroblasts (RVfib) are unknown. Activation of the mitochondrial fission mediator dynamin-related protein 1 (Drp1) contributes to dysfunction of RV myocytes in PAH through...
Article
The following review summarizes the pro-con debate about current controversies regarding the pathogenesis of pulmonary arterial hypertension (PAH) that took place at the American Thoracic Society Conference in May 2017. Leaders in the field of PAH research discussed the importance of the immune system, the role of hemodynamic stress and endothelial...