A5035022479- Pulmonary Hypertension Research and Treatments
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Cardiovascular Disease and Adiposity
- ATP Synthase and ATPases Research
- Cardiovascular Function and Risk Factors
- MicroRNA in disease regulation
- Long-Term Effects of COVID-19
- Apelin-related biomedical research
- Hemoglobinopathies and Related Disorders
- Cardiomyopathy and Myosin Studies
- Liver Disease and Transplantation
- Epigenetics and DNA Methylation
- Biomarkers in Disease Mechanisms
- Infectious Encephalopathies and Encephalitis
- Cardiovascular Issues in Pregnancy
- Infective Endocarditis Diagnosis and Management
- Frequency Control in Power Systems
- Adenosine and Purinergic Signaling
- Liver physiology and pathology
- Nitric Oxide and Endothelin Effects
- Hormonal Regulation and Hypertension
- Eosinophilic Disorders and Syndromes
- Legionella and Acanthamoeba research
- Inflammasome and immune disorders
Queen's University
2020-2024
Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF PAH. Objectives: Evaluating the contribution of inflammasome RV macrophages to PAH RVF. Methods: Rats with decompensated hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared compensated rats (pulmonary artery banding)....
The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-
Neutrophils play a role in innate immunity and are critical for clearance of Staphylococcus aureus. Current understanding neutrophil bactericidal effects is that NADPH oxidase produces reactive oxygen species (ROS), mediating bacterial killing. also contain numerous mitochondria; since these organelles lack oxidative metabolism, their function unclear. We hypothesize mitochondria human neutrophils contribute to the capacity S. aureus.and Findings: Using isolated from healthy volunteers (n =...
Impaired mitochondrial fusion, due in part to decreased mitofusin 2 (Mfn2) expression, contributes unrestricted cell proliferation and apoptosis-resistance hyperproliferative diseases like pulmonary arterial hypertension (PAH) non-small lung cancer (NSCLC).We hypothesized that Mfn2 levels are reduced increased proteasomal degradation of triggered by its phosphorylation at serine 442 (S442) investigated the potential kinase mediators.Mfn2 expression was S442 artery smooth muscle cells from...
Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in arterial hypertension (PAH). We developed potent GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy PAH are unknown.
Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There limited understanding of the molecular mechanisms RVF PAH. Methods: In a PAH-RVF model induced by injection adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectrometry to identify proteins change RV as consequence PAH RVF. Bioinformatic analysis was used integrate our previously published RNA sequencing data independent...
Introduction: Mitochondrial fission is mediated by dynamin related protein-1 (Drp1) activation; however, to complete fission, we have evidence that Drp1 requires assistance from the GTPase 2 (DNM2). Hypothesis: DNM2 interacts with regulate mitotic and cell cycle progression, permitting hyperproliferative phenotype of pulmonary artery smooth muscle cells (PASMC) in arterial hypertension (PAH). Methods: Colocalization was assessed using STED super resolution confocal microscopy. Interaction...
Background: Epigenetic changes in gene expression due to DNA methylation regulate pulmonary vascular structure and function. Genetic or acquired alterations demethylation promote development of arterial hypertension (PAH). However, the methylome signature human PAH its transcriptomic consequences are unknown. Methods: Reduced Representation Bisulfite Sequencing was used for epigenome-wide mapping whole peripheral blood 10 healthy people 20 age/sex matched patients from Biobank. We...
Introduction: Dynamin-related protein 1 (Drp1) activation increases mitochondrial fission and cell cycle progression in hyperproliferative cells, termed mitotic fission. However, the diameter of a apparatus comprised solely Drp1 its binding partners appears insufficient to complete Moreover, mechanism linking is unknown, suggesting an additional mediator terminal steps Hypothesis: The large GTPase, dynamin 2 (DNM2), interacts with regulate progression. Corollary: DNM2 epigenetically...
Background: Pulmonary Arterial Hypertension (PAH) is a fatal cardiopulmonary disorder characterized by adverse vascular remodelling of small pulmonary arteries, which increases resistance and demand on the right ventricle (RV), ultimately leading to RV fibrosis failure. Emerging evidence suggests that inflammation plays crucial role in PAH pathogenesis. Here, we study Clonal Hematopoiesis Indeterminate Potential (CHIP), somatic mutations genes such as DNMT3A TET2 , promotes an inflammatory...
Background: Mutations are found in 10-20% of idiopathic PAH (IPAH) patients, but none identified connective tissue disease-associated (APAH), which accounts for ~45% cases. TET2 mutations, a cause clonal hematopoiesis indeterminant potential (CHIP), predispose to an inflammatory type PAH. We now examine mutations another CHIP gene, DNMT3A, Methods: assessed DNMT3A mutation prevalence Biobank subjects as compared with controls, first using whole exome sequencing (WES)-derived calls 1832...
Introduction: Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission contributes to the pathogenesis of pulmonary arterial hypertension (PAH). We investigated pharmacokinetic characteristics Drpitor1a, a novel, small molecule, ellipticine Drp1 inhibitor (prepared in-house), and tested its therapeutic efficacy in pilot study using rat monocrotaline (MCT)-PAH model. Methods: A single dose Drpitor1a (5mg/kg) was administered IV or PO male female rats (n=3/sex). Blood...
Background: Pulmonary Arterial Hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary arteries. Increasing evidence suggests that inflammation plays an essential role in PAH development. Understanding involvement immunity this context can provide valuable insights into pathogenesis PAH. DNA Methyltransferase 3A ( DNMT3A ) mutations lead to altered methylation patterns immune cells, potentially affecting expression immune-regulatory genes. Here, we...
Background: The right ventricle (RV) fails in pulmonary arterial hypertension (PAH) part due to inflammation. In male PAH, RV CCR2 + macrophages induce inflammation via NLRP3 inflammasome. Since PAH males have worse outcomes, a cardioprotective role of the female sex hormones is suggested. Hypothesis: Ovariectomy (OVX) females recapitulates males’ disease severity by increasing inhibition ameliorates function and OVX rats with monocrotaline (MCT)-induced PAH. Methods: was induced MCT...
Abstract Rationale Dynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes arterial hypertension (PAH). We developed Drp1 inhibitor, Drpitor1a, and tested its ability regress PAH. Objectives Assess Drpitor1a’s efficacy toxicity in: a)normal PAH human PASMC (hPASMC); b)normal rats versus with established...
Introduction: The obstructive vasculopathy in pulmonary arterial hypertension (PAH) results part from acquired mitochondrial changes smooth muscle cells (PASMC), including increased mitotic fission. Mitotic fission, division which is coordinated with mitosis to equitably distribute mitochondria daughter cells, mediated by activation of dynamin-related protein 1 (Drp1). To complete Drp1 requires assistance the GTPase dynamin 2 (DNM2). Hypothesis: Pathological increase DNM2 expression drives...
Introduction: Dynamin-related protein 1 (DRP1) is a large GTPase that mediates mitotic fission (the division of mitochondria which coordinated with mitosis, ensuring equitable distribution to daughter cells). In pulmonary arterial hypertension (PAH) artery smooth muscle cells (PASMC), fission, and DRP1 activity are increased, contributing its hyperproliferative phenotype. We investigated the therapeutic efficacy Drpitor1a, novel, small molecule, Drp1 inhibitor, in rat PAH model. Methods: A...
Background: Pulmonary Arterial Hypertension (PAH) is an obliterative pulmonary vasculopathy in which structural changes are driven by inflammation, fibrosis, mitochondrial dysfunction, and pathological angiogenesis. While ~10% of cases PAH have germline BMPR2 mutations (or one 16 other recognized or putative genes), the genetic basis for majority patients remains unexplained. Somatic hematopoietic stem cells (HSC) related to disorders clonal hematopoiesis indeterminate potential (CHIP). Tet...
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by cellular remodeling in the pulmonary circulation. vascular obstruction, stiffening and constriction elevate artery pressure right ventricular (RV) afterload leading to failure (RVF). In model of PAH induced injection monocrotaline (MCT, 60mg/kg sc) RV decompensation was confirmed. Then proteome analyzed using Mass Spectrometry (LC-MSMS). Proteomics revealed 1,277 differentially regulated proteins. Integration this...
Introduction: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy that causes right ventricle failure (RVF) and death. This study evaluates the role of pyrin domain-containing protein 3 (NLRP3) inflammasome activation within RV macrophages in RVF. Hypothesis: In PAH, NLRP3 activated infiltrating contributes to Methods: We compared inflammation monocrotaline (MCT=25; PBS=21) rats, which have decompensated hypertrophy (RVH), artery banding (PAB=11; Sham=11)...