A5009299943- Nitric Oxide and Endothelin Effects
- Circadian rhythm and melatonin
- Sphingolipid Metabolism and Signaling
- Eicosanoids and Hypertension Pharmacology
- Spaceflight effects on biology
- Cellular transport and secretion
- Cardiovascular Health and Disease Prevention
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Protein Kinase Regulation and GTPase Signaling
- Intracranial Aneurysms: Treatment and Complications
- Adenosine and Purinergic Signaling
- Atherosclerosis and Cardiovascular Diseases
- Traumatic Brain Injury and Neurovascular Disturbances
- Workplace Health and Well-being
- Antioxidant Activity and Oxidative Stress
- S100 Proteins and Annexins
- Free Radicals and Antioxidants
- Cell Adhesion Molecules Research
- Retinoids in leukemia and cellular processes
- Neuroinflammation and Neurodegeneration Mechanisms
- Connective tissue disorders research
- Takotsubo Cardiomyopathy and Associated Phenomena
- Sleep and Work-Related Fatigue
- Thermoregulation and physiological responses
- Climate Change and Health Impacts
University of Toronto
2011-2022
Ted Rogers Centre for Heart Research
2019-2022
Canada Research Chairs
2017
Toronto General Hospital Research Institute
2010-2012
St Michael's Hospital
2012
Toronto Centre for Phenogenomics
2012
Princess Margaret Hospital
2012
Toronto General Hospital
2010-2012
University of Waterloo
2007-2012
St. Michael's Hospital
2010-2012
The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease worse outcomes. However, the role of generally clinically unappreciated. Clock core component here we examine as vital determinant cardiac pathophysiology aging. ClockΔ19/Δ19 mice develop age-dependent increases weight, hypertrophy, dilation, impaired contractility, reduced myogenic responsiveness. Young hearts express dysregulated mRNAs miRNAs PTEN-AKT...
Mechanisms underlying vasomotor abnormalities and increased peripheral resistance exacerbating heart failure (HF) are poorly understood.To explore the role molecular basis of myogenic responses in HF.10 weeks old C57Bl6 mice underwent experimental myocardial infarction (MI) or sham surgery. At 1 to 12 postoperative, hemodynamic studies, mesenteric, cerebral, cremaster artery perfusion myography Western blot. Organ weights hemodynamics confirmed HF after MI. Myogenic responses, ie,...
Background— Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay its generating enzyme sphingosine kinase 1 and functional antagonist phosphohydrolase-1. The intracellular localization phosphohydrolase-1 necessitates import extracellular into compartment before degradation. present investigation proposes that cystic fibrosis transmembrane conductance transports hence...
Background— Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in early stages of heart failure, particularly when pressure minimally affected, are not known. Methods and Results— Using a myocardial infarction model mice, we demonstrate tumor necrosis factor-α (TNFα)–dependent enhancement posterior artery tone that reduces before any overt changes brain structure function. TNFα...
Objectives: AMP-activated protein kinase (AMPK) activity may alter blood pressure by directly influencing vascular tone. The purpose of this study is to examine if these effects occur acutely in a model hypertension. Methods and results: Using distinct groups Wistar–Kyoto rats (WKY) spontaneously hypertensive (SHR) we compare baseline aortic mesenteric artery AMPK activation (by immunoblotting), hemodynamic (blood heart rate via carotid catheter) biochemical responses an acute injection...
Abstract Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively regulates signalling systemic haemodynamics under non-pathological settings. Here we show acutely deleting gene or pharmacologically scavenging...
Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between artery cystic fibrosis transmembrane conductance regulator (CFTR) expression altered cerebrovascular reactivity in HF SAH. In SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations expression, vascular reactivity, without affecting systemic hemodynamic parameters. normalization...
Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to microcirculation. We demonstrate skeletal muscle resistance arteries isolated from patients diabetes have augmented tone, despite reasonable blood glucose control. To understand mechanisms, we titrated a standard mouse model (high-fat diet...
The objective of this study was to test the hypothesis that effect a high-fat meal (HFm) on plasma lipid-soluble antioxidants and biomarkers vascular oxidative stress inflammation would be attenuated by short-term lycopene supplementation in young healthy subjects. Following restriction lycopene-containing foods for 1-wk (LYr), blood collected fasting state 3 h after HFm low-fat (LFm) N = 18 men aged 23 +/- 2 years, only 9 women 1 years. Blood also sampled pre- post-meals following 80 mg/day...
Objective— The purpose of this study was to characterize a phosphorylation motif at serine 225 as molecular switch that regulates the pressure-dependent activation sphingosine kinase 1 (Sk1) in resistance artery smooth muscle cells. Methods and Results— In isolated hamster gracilis arteries, activation/translocation Sk1 by ERK1/2 critically dependent on its site. Specifically, expression S225A reduced resting myogenic tone, Ca 2+ , pressure-induced elevations, sensitivity. lack function...
In this study we investigated the role of circadian mechanism on cognition-relevant brain regions and neurobiological impairments associated with heart failure (HF), using murine models. We found that is an important regulator healthy cognitive system neurobiology. Normal Clock∆19/∆19 mice had neurons smaller apical dendrite trees in medial prefrontal cortex (mPFC), hippocampus, showed impaired visual-spatial memory, exhibited lower cerebrovascular myogenic tone, versus wild types (WT). then...
Arterial stiffening is a significant predictor of cardiovascular disease development and mortality. In elastic arteries, refers to the loss fragmentation fibers, with progressive increase in collagen fibers. Type VIII (Col-8) highly expressed developmentally, then once again dramatically upregulated aged diseased vessels characterized by arterial stiffening. Yet its biophysical impact on vessel wall remains unknown. The purpose this study was test hypothesis that Col-8 functions as matrix...
Abstract Aims Circadian rhythms orchestrate important functions in the cardiovascular system: contribution of microvascular to disease progression/severity is unknown. This study hypothesized that (i) myogenic reactivity skeletal muscle resistance arteries rhythmic and (ii) disrupting this rhythmicity would alter cardiac injury post-myocardial infarction (MI). Methods results Cremaster were isolated assessed using standard pressure myography. was globally disrupted with ClockΔ19/Δ19 mutation...
Subarachnoid hemorrhage (SAH) is a devastating cerebral event caused by an aneurysmal rupture. In addition to neurological injury, SAH has significant effects on cardiac function and the peripheral microcirculation. Since these complications may exacerbate brain prevention management of are important for improving overall clinical outcome after SAH. this investigation, we examined vascular reactivity in well-characterized blood injection model Standard echocardiographic pressure measurement...
A hallmark of heart failure (HF) is elevated peripheral resistance, which primarily results from an augmented myogenic response (MR, the intrinsic property resistance arteries (RA) to adapt diameter changes in pressure). In cerebral HF mice, tumor necrosis factor α (TNFα) plays a central role for enhancement MRs (through activation sphingosine kinase‐1). We hypothesized that TNFα equally important augmentation skeletal muscle RA and hence, increased HF. was induced Male C57/BL6 mice through...
The increase in vascular resistance observed heart failure primarily results from an enhanced myogenic response (MR), the intrinsic property of arteries (RA) to adapt their diameter and hence, resistance, changes pressure. We have recently shown that cytokine tumor necrosis factor α (TNFα) augments MR by activating sphingosine kinase‐1 (Sk1). hypothesized TNFα‐Sk1 axis also operates under physiological conditions TNFα is integral signaling element underlying MR. Isolated hamster RA (n=6)...
Hydrogen peroxide (H 2 O ) is an endogenous endothelium‐dependent dilator in resistance vessels; however, a role for H the mesenteric vessels of spontaneously hypertensive rat (SHR) has not been established. Mesenteric arteries were excised from SHR and normotensive (WKY) rats myography was performed. Vessels incubated with 3μM β‐blocker propranolol, pre‐contracted norepinephrine, cumulative dose‐response curves acetylcholine (Ach) conducted. Maximal dilation to Ach impaired compared WKY...
Endothelium-derived hyperpolarizing factor (EDHF) contributes to vascular dilation but its chemical identity is unknown. Decreased EDHF-mediated dilation, assessed with inhibited prostaglandin and nitric oxide production, may lead impaired vasomotion in spontaneously hypertensive rats (SHR). Mesenteric arteries were excised from SHR normotensive (WKY) myography was performed. Vessels incubated 3μM of the β-blocker propranolol, pre-contracted norepinephrine, cumulative dose-response curves...