A5108604623- Phosphodiesterase function and regulation
- Receptor Mechanisms and Signaling
- Nitric Oxide and Endothelin Effects
- Renin-Angiotensin System Studies
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Platelet Disorders and Treatments
- Cholinesterase and Neurodegenerative Diseases
- Blood Pressure and Hypertension Studies
- Synthesis and Catalytic Reactions
- Mast cells and histamine
- Protein Kinase Regulation and GTPase Signaling
- Cell Adhesion Molecules Research
- Regulation of Appetite and Obesity
- Adenosine and Purinergic Signaling
- Protease and Inhibitor Mechanisms
- Antiplatelet Therapy and Cardiovascular Diseases
- Pulmonary Hypertension Research and Treatments
- Angiogenesis and VEGF in Cancer
- Apelin-related biomedical research
- Peptidase Inhibition and Analysis
- 14-3-3 protein interactions
- Dietary Effects on Health
- Cardiovascular Issues in Pregnancy
- Heart Failure Treatment and Management
- Neuropeptides and Animal Physiology
Queen's University
2014-2025
University of Calgary
2007-2011
University Health Network
2007-2011
University of Toronto
2007-2011
University of Utah
2011
National Heart Lung and Blood Institute
2011
National Institutes of Health
2011
University of California, San Francisco
2011
Kingston Health Sciences Centre
2010
Institute of Pharmacology
2008
We investigated the roles of cyclic GMP and AMP in inhibition rabbit platelet aggregation degranulation by two nitrovasodilators, sodium nitroprusside (SNP) 3-morpholinosydnonimine (SIN-1; active metabolite molsidomine), with particular reference to synergistic interaction these drugs prostaglandin E1 (PGE1). Changes [3H]GMP [3H]AMP were measured rapid sensitive prelabeling techniques, validity which confirmed radioimmunoassays. Incubation platelets 0.1 10 microM SNP alone for 0.5 min caused...
Studies on the physiological role of heme oxygenase (HO) require an inhibitor that will selectively inhibit HO activity without inhibiting either nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). The objective this study was to test a series metalloporphyrins have previously been shown activity, for their ability NOS sGC activities. Measurement in rat brain microsomes and cytosol made samples incubated with (0.15-50 microM), including zinc protoporphyrin IX, deuteroporphyrin IX...
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)....
SPARC, a matricellular protein that affects cellular adhesion and proliferation, is produced in remodeling tissue pathologies involving fibrosis angiogenesis. In this study we have asked whether peptides generated from cleavage of SPARC the extracellular milieu can regulate Matrix metalloproteinase (MMP)-3, but not MMP-1 or 9, showed significant activity toward SPARC. Limited digestion recombinant human (rhu)SPARC with purified catalytic domain rhuMMP-3 three major fragments, which were...
Angiogenesis is necessary during embryonic development and wound healing but can be detrimental in pathologies, including cancer. Because initiation of angiogenesis involves migration proliferation vascular endothelial cells (VECs) cAMP-elevating agents inhibit these events, such may represent a novel therapeutic avenue to controlling angiogenesis. Intracellular cAMP levels are regulated by their synthesis adenylyl cyclases hydrolysis cyclic nucleotide phosphodiesterases (PDEs). In this...
We recently showed that phosphoinositide-3-kinase-gamma-deficient (PI3Kgamma(-/-)) mice have enhanced cardiac contractility attributable to cAMP-dependent increases in sarcoplasmic reticulum (SR) Ca(2+) content and release but not L-type current (I(Ca,L)), demonstrating PI3Kgamma locally regulates cAMP levels cardiomyocytes. Because phosphodiesterases (PDEs) can contribute compartmentation, we examined whether the PDE activity was altered by ablation. Selective inhibition of PDE3 or PDE4...
Rationale: Baseline contractility of mouse hearts is modulated in a phosphatidylinositol 3-kinase-γ–dependent manner by type 4 phosphodiesterases (PDE4), which regulate cAMP levels within microdomains containing the sarcoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a). Objective: The goal this study was to determine whether PDE4D regulates basal cardiac contractility. Methods and Results: At 10 12 weeks age, baseline PDE4D-deficient (PDE4D −/− ) mice elevated vivo Langendorff perfused...
Vascular endothelial cell (VEC) permeability is largely dependent on the integrity of vascular cadherin (VE-cadherin or VE-Cad)-based intercellular adhesions. Activators protein kinase A (PKA) exchange activated by cAMP (EPAC) reduce VEC stabilizing VE-Cad-based Currently, little known concerning nature and composition signaling complexes that allow PKA EPAC to regulate structures through these actions control permeability. Using pharmacological, biochemical, biological approaches we...
A combination of pharmacological, molecular biological and biochemical approaches were used to investigate the differential expression two cyclic GMP‐inhibited nucleotide phosphodiesterase genes (PDE3A PDE3B) in rat. RT–PCR using PDE3A‐ or PDE3B‐specific oligonucleotide primers allowed amplification products encoding PDE3A (508 bp) PDE3B (499 sequences from several rat tissues (heart, aorta, liver, kidney epididymal fat), primary cultures aortic vascular smooth muscle cells (VSMC) as well an...
Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that strongly linked to mutations in BMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective ligand, BMP9, reverses animal models pulmonary and suppresses proliferation healthy endothelial cells. However, impact loss on antiproliferative actions BMP9 has yet be assessed. Approach Results: suppressed blood outgrowth cells from control subjects...
Although phosphodiesterase 4 (PDE4) inhibitors have reached the clinic, their lack of selectivity for PDE4 enzyme isoforms leads to documented side effects. Building in has proved difficult because all enzymes share highly conserved catalytic domains. The report by Sin et al. describes a novel approach which potent proteolysis targeting chimera (PROTAC) selectively promotes degradation small subset (i.e., "short forms") and impacts inflammatory events regulated these enzymes. This offers...
Abstract —Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze cAMP or cGMP and terminate their signaling. Two important families of PDEs that regulate signaling in cardiovascular tissues are the cGMP-inhibited (PDE3) cAMP-specific (PDE4). In this study, we have used a combination an vitro motility assay sensitive method for measurement order to determine relative roles PDE3 PDE4 regulation cAMP-mediated inhibition VSMC migration. Our data demonstrate forskolin, activator adenylyl cyclases,...
In this study, we describe a novel mechanism by which protein kinase C (PKC)-mediated activation of the Raf-extracellular signal-regulated (MEK)-extracellular (ERK) cascade regulates activity and membrane targeting members cyclic AMP-specific phosphodiesterase D family (PDE4D). Using combination pharmacological biochemical approaches, show that increases in intracellular cAMP cause A-mediated phosphorylation two PDE4D variants expressed vascular smooth muscle cells, namely PDE4D3 PDE4D5....
Multiple families of cyclic nucleotide phosphodiesterases (PDE) have been described, and the regulated expression these genes in cells is complex. Although cAMP known to control certain PDE cells, presumably reflecting a system feedback on signaling, relatively little about influence non-cAMP signaling systems expression. In this study, we describe novel mechanism by which activators protein kinase C (PKC)-Raf-MEK-ERK cascade regulate phosphodiesterase 4D (PDE4D) vascular smooth muscle...
An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation a major cause acute coronary events and was shown previously to facilitate ADP-induced platelet aggregation, we chose define signaling involved in leptin-mediated activation. Using pharmacological, biochemical, cell biological approaches, show that leptin-induced activation required cascade included long form receptor, three...
It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (SNP), or phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their on cGMP, agents sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might cGMP. Our data an integral component protein kinase G1β...
cAMP regulates integrin-dependent adhesions of vascular endothelial cells (VECs) to extracellular matrix proteins, their cadherin-dependent intercellular adhesions, and proliferation migration in response growth chemotactic factors. Previously, we reported that cAMP-elevating agents differentially inhibited human VECs isolated from large structures (macro-VECs, aortic [HAECs]) or small (micro-VECs, microvascular [HMVECs]) hydrolysis by phosphodiesterase (PDE)3 PDE4 enzymes was important...