A5032824868- Mitochondrial Function and Pathology
- Autophagy in Disease and Therapy
- Cell death mechanisms and regulation
- Chemotherapy-induced cardiotoxicity and mitigation
- ATP Synthase and ATPases Research
- Cardiac Ischemia and Reperfusion
- NF-κB Signaling Pathways
- Cancer, Hypoxia, and Metabolism
- Cardiac electrophysiology and arrhythmias
- Signaling Pathways in Disease
- Adipose Tissue and Metabolism
- Ubiquitin and proteasome pathways
- Cardiac Fibrosis and Remodeling
- Circadian rhythm and melatonin
- Ion channel regulation and function
- Cardiovascular Function and Risk Factors
- Cancer-related Molecular Pathways
- Cardiomyopathy and Myosin Studies
- Congenital heart defects research
- Immune Response and Inflammation
- Electron Spin Resonance Studies
- RNA modifications and cancer
- Virus-based gene therapy research
- Peptidase Inhibition and Analysis
- Cardiac Structural Anomalies and Repair
University of Manitoba
2016-2025
St. Boniface Hospital
2015-2024
Baum Consult
2011-2018
Research Institute of General Pathology and Pathophysiology, the Russian Academy of Medical Sciences
2014
Research Manitoba
2012-2013
Therapeutics Clinical Research
2012
University Health Network
2004-2011
St. Michael's Hospital
2007
University of Toronto
2004-2007
Western University
2003-2007
Pressure overload is accompanied by cardiac myocyte apoptosis, hypertrophy, and inflammatory/fibrogenic responses that lead to ventricular remodeling heart failure. Despite incomplete understanding of how this process regulated, the upregulation tumor necrosis factor (TNF)-alpha after aortic banding in myocardium known. In present study, we tested our hypothesis TNF-alpha regulates inflammatory response, extracellular matrix homeostasis, hypertrophy response mechanical contributes...
Following myocardial infarction, nonischemic myocyte death results in infarct expansion, loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes remodeling the mouse, despite having no effect on early or late size. We evaluated effects of ablating Bnip3 cardiomyocyte death, size, after surgical ischemia/reperfusion (IR) injury mice. Immediately following IR, significant differences were observed between Bnip3–/– WT However, at 2 days...
Significance We provide new, exciting evidence for a previously unidentified signaling pathway that mechanistically links mitochondrial respiratory chain defects to necrosis and heart failure induced by the chemotherapy agent doxorubicin (DOX). specifically show DOX disrupts protein complexes between key proteins, including uncoupling 3 cytochrome c oxidase, resulting in abnormal respiration through mechanism contingent on Bcl-2-like 19kDa-interacting (Bnip3). Perhaps most compelling is our...
In this study, we provide evidence for the operation of BNIP3 as a key regulator mitochondrial function and cell death ventricular myocytes during hypoxia. contrast to normoxic cells, 5.6-fold increase ( P <0.05) in myocyte was observed cells subjected Moreover, significant expression detected postnatal adult rat hearts An vivo with chronic heart failure. Subcellular fractionation experiments indicated that endogenous integrated into membranes Adenovirus-mediated delivery full-length...
Yeast silent information regulator 2 (Sir2), a nicotinamide adenine dinucleotide-dependent histone deacetylase (HDAC) and founding member of the HDAC class III family, functions in wide array cellular processes, including gene silencing, longevity, DNA damage repair. We examined whether or not mammalian ortholog Sir2 affects growth death cardiac myocytes. Cardiac myocytes express Sir2alpha predominantly nucleus. Neonatal rat were treated with 20 mmol/L (NAM), inhibitor, 50 nmol/L...
Background— We investigated the potential contributions of tumor necrosis factor-α (TNF-α) on incidence acute myocardial rupture and subsequent chronic cardiac dysfunction after infarction (MI) in TNF knockout (TNF −/− ) mice compared with C57/BL wild-type (WT) mice. Methods Results— Animals were randomized to left anterior descending ligation or sham operation killed days 3, 7, 14, 28. monitored rate, function, inflammatory response, collagen degradation, net formation. found following: (1)...
One of the major manifestations obesity is increased production adipocyte-derived 16-kDa peptide leptin, which also elevated in heart disease, including congestive failure. However, whether leptin can directly alter cardiac phenotype not known. We therefore studied effect as a potential hypertrophic factor cultured myocytes from 1- to 4-day-old neonatal rat ventricles. Using RT-PCR, we demonstrate that these cells express short-form (OB-Ra) receptor. Twenty-four hours exposure (0.31 31.3...
Background To formally test whether the antiapoptotic protein bcl-2 would prevent programmed cell death in cardiac muscle cells provoked by p53, a known trigger of apoptosis variety different types, we used replication defective adenovirus encoding either and p53 genes to deliver ventricular myocytes with high efficiency uniformity. Methods Results Vital staining revealed significant (7-fold, P <.05) increase myocyte presence contrast uninfected or those infected control virus. In...
Irreversible exit from the cell cycle precludes ability of cardiac muscle cells to increase number after infarction. Using adenoviral E1A, we previously demonstrated dual pocket protein- and p300-dependent pathways in neonatal rat myocytes, have proven that E2F-1, which occupies Rb pocket, suffices for these actions E1A. By contrast, susceptibility adult ventricular viral delivery exogenous regulators has not been tested, vitro or vivo. In cultured gene transfer E2F-1 induced expression...
Background: Over the past several years, a variety of human and animal studies have shown that circadian clocks regulate biological cardiovascular rhythms in both health disease. For example, heart rate blood pressure fluctuate over 24-hour daily periods, such levels are higher morning progressively decline evening. Methods Results: It is interesting to note timing administration various cardiac treatments can also benefit some outcomes. Circadian been implicated pathogenesis number...
Cardiac function is highly reliant on mitochondrial oxidative metabolism and quality control. The circadian Clock gene critically linked to vital physiological processes including fission, fusion bioenergetics; however, little known of how the regulates these in heart. Herein, we identified a putative CLOCK-mitochondrial interactome that gates an adaptive survival response during myocardial ischemia. We show by transcriptome ontology mapping CLOCK Δ19/Δ19 mouse transcriptionally coordinates...
Myocardial ischemia-reperfusion (I/R) injury increases the generation of oxidized phosphatidylcholines (OxPCs), which results in cell death. However, mechanism by OxPCs mediate death and cardiac dysfunction is largely unknown. The aim this study was to determine mechanisms OxPC triggers cardiomyocyte during reperfusion injury. Adult rat ventricular cardiomyocytes were treated with increasing concentrations various purified fragmented OxPCs. Cardiomyocyte viability, bioenergetic response,...
Abstract Mitofusins reside on the outer mitochondrial membrane and regulate fusion, a physiological process that impacts diverse cellular processes. are activated by conformational changes subsequently oligomerize to enable fusion. Here, we identify small molecules directly increase or inhibit mitofusins activity modulating mitofusin conformations oligomerization. We use these better understand role of in function, signaling. find activation increases, whereas inhibition decreases fusion...
Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial nuclear factor-κB...
Molecular dissection of mechanisms that govern the differentiated cardiac phenotype has, for cogent technical reasons, largely been undertaken to date in neonatal ventricular myocytes. To circumvent expected limitations other methods, present study was initiated determine whether replication-deficient adenovirus would enable efficient gene transfer adult cells culture. Adult rat myocytes were infected, 24 h after plating, with type 5 containing a cytomegalovirus immediate-early...
The dose-dependent cardiomyopathy and heart failure due to adriamycin have been shown be increased oxidative stress loss of myocytes. We examined the incidence myocardial apoptosis as well changes in expression apoptotic regulatory gene products an established animal model cardiomyopathy. Rats were treated with (cumulative dose, 15 mg/kg), hearts for Bax, caspase 3, Bcl-2 at 0, 4, 10, 16, 21 days after treatment. A significant increase was seen 4 days, followed by a decline 10 16...
Fas and ligand (FasL) expression has been detected in chronic vascular lesions, Fas-mediated apoptosis of smooth muscle cells (VSMC) may influence the integrity atherosclerotic plaque. Here we report that FasL is not expressed by normal VSMC, but its upregulated stresses induce apoptosis, including serum deprivation, exposure to phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, ablation Akt signaling. Conversely, constitutive activation signaling diminished VSMC cultures...