Cardioprotective effects of pde-5 inhibitors

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Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL079424-04
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Description:
[unreadable] (provided by applicant): Phosphodiesterase-5 (PDE-5) inhibitor, sildenafil (Viagra), which is known to enhance erectile function in men, induces powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in heart. We propose to perform further in depth studies on the mechanisms by which sildenafil and other clinically used PDE-5 inhibitors trigger signaling pathways that lead to cardioprotection. Hypothesis 1: Novel class of PDE-5 inhibitors trigger protection against I/R in heart and myocytes. We will study the effect of short acting (sildenafil, verdenafil) or long-acting (tadalafil) PDE-5 inhibitors on protective effect against I/R and apoptosis. Hypothesis 2: Release of preconditioning mediators, including adenosine, bradykinin and nitric oxide mediate cardioprotection induced by PDE-5 inhibitors. Using pharmacological inhibitors and gone knockout mice of adenosine A1, bradykinin B2 receptors, eNOS, nNOS and iNOS. we will determine the direct role of these mediators in cardioprotection by PDE-5 inhibitors. Hypothesis 3: PDE-5 inhibitors selectively activate PKC isoforms that play an essential role in the gene transcription of eNOS/iNOS/nNOS to induce cardioprotective effect. We will study translocation of PKC isozymes after treatment with PDE-5 inhibitors. Using selective peptide blockers of PKC isozymes, we will determine their role in gone transcription of eNOS, iNOS or nNOS. Hypothesis 4:PDE-5 inhibitors stimulate guanylate cyclase and elevate cGMP causing activation of protein kinase G (PKG) as a prelude to the opening of mitoKATP channels. Using adenoviral gene transfer of splice variants of PKG or their null mutants, we will determine their role in protection against I/R in cardiomyocytes and intact heart. Hypothesis 5:PDE-5 inhibitors protect against I/R by overexpression of HSPs through activation of transcription factor, HSF-1. Using siRNAs, we will determine the cause and effect relationship of HSF-1 in cardioprotection by PDE-5 inhibitors in mice. These studies, first of its kind, will provide tremendous amount of new information on protective effect of PDE-5 inhibitors against I/R injury. It is expected that the studies will have enormous impact on bringing the long-studied phenomenon of ischemic and pharmacologic preconditioning to the clinical forefront. [unreadable] [unreadable]
 
Project Terms:
1-((3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine citrate 70-kD Heat-Shock Protein Abbott brand of sildenafil citrate Acute Adenosine After Care After-Treatment Aftercare Apoptosis Apoptosis Pathway Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg B2R BDKRB2 BK-2 BK2 BKR2 BRB2 Biochemistry Bradykinin Bradykinin B2 Receptor Bradykinin Type 2 Receptor Calcium Phospholipid-Dependent Protein Kinase Calcium-Activated Phospholipid-Dependent Kinase Cardiac Myocytes Cardiac infarction Cardiocyte Cardiovascular Diseases Cause of Death Cell Communication and Signaling Cell Death, Programmed Cell Signaling Chemistry, Biological Chronic Circulatory Collapse Class Clinical Cultured Cells Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cytosol DNA Molecular Biology Deep Deoxyguanylate Cyclase Depth Developed Countries Developed Nations Developing Countries Developing Nations Dose Drugs EC 2.7 Endogenous Nitrate Vasodilator Endothelium-Derived Relaxing Factor Enzymes Erectile dysfunction Exhibits FDA Food and Drug Administration Food and Drug Administration (U.S.) Future G-Proteins GTP pyrophosphate-lyase (cyclizing) GTP-Binding Proteins GTP-Regulatory Proteins GUCY Gene Transcription Gene Transfer Generations Genetic Transcription Genetically Engineered Mouse Guanine Nucleotide Coupling Protein Guanine Nucleotide Regulatory Proteins Guanosine Cyclic 3',5'-Monophosphate Guanosine Cyclic 3',5'-Phosphate-Dependent Protein Kinase Guanosine Cyclic Monophosphate Guanosine Cyclic Monophosphate-Dependent Protein Kinases Guanosine, cyclic 3',5'-(hydrogen phosphate) Guanyl Cyclase Guanylate Cyclase HO-1 enzyme HO1 HO2 HSF-1 HSF1 HSP HSP 70 HSP32 HSP70 Haem Oxygenase Hearing Heart Heart myocyte Heat shock proteins Heat-Shock Proteins 70 Heme Oxygenase (Decyclizing) Heme,hydrogen-donor[{..}]oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating) Hepatocyte Nitric Oxide Synthase INOS Inducible Nitric Oxide Synthase Industrialized Countries Industrialized Nations Injury Inosinate Cyclase Intracellular Communication and Signaling Ischemia Ischemia-Reperfusion Injury Ischemic Heart Ischemic Heart Disease Ischemic Preconditioning Ischemic myocardium Isoenzymes Isoforms Isozymes Kinases Knockout Mice Knowledge Lead Less-Developed Countries Less-Developed Nations Macrophage Nitric Oxide Synthase Mammals, Mice Mammals, Rabbits Mediating Mediator Mediator of Activation Mediator of activation protein Medication Membrane Methods and Techniques Methods, Other Mice Mice, Knock-out Mice, Knockout Mining Minings Mitochondria Molecular Molecular Biology Mononitrogen Monoxide Murine Mus Muscle Cells Muscle Cells, Cardiac Muscle Cells, Heart Muscle Cells, Mature Muscle, Cardiac Muscle, Heart Myocardial Myocardial Infarct Myocardial Infarction Myocardial Ischemia Myocardium Myocytes Myocytes, Cardiac NOS Type II NOS2 NOS2A NOS2A protein, human Necrosis Necrotic Nitric Oxide Nitric Oxide Synthase 2A Nitric Oxide, Endothelium-Derived Nitrogen Monoxide Nitrogen Protoxide Nitrogen oxide Null Mouse Numbers Oryctolagus cuniculus Overexpression PDE 5 enzyme PKC PKG Pb element Peptides Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Phase Phospholipid-Sensitive Calcium-Dependent Protein Kinase Phosphorylation Phosphotransferases Physiological reperfusion Physiology Play Preconditionings, Ischemic Protein Isoforms Protein Kinase C Protein Kinase G Protein Overexpression Protein Phosphorylation Purpose RNA Expression RNA Splicing RNA, Small Interfering Rabbit, Domestic Rabbits Receptor Protein Reperfusion Damage Reperfusion Injury Reperfusion Therapy Role Shock Signal Pathway Signal Transduction Signal Transduction Systems Signaling Sildenafil citrate Silenafil Citrate Simulate Small Interfering RNA Soluble Guanylate Cyclase Soluble Guanylyl Cyclase Splicing Stress Proteins Techniques Third-World Countries Third-World Nations Time Today Transcription Transcription, Genetic Transphosphorylases UC01 USFDA Under-Developed Countries Under-Developed Nations United States Food and Drug Administration Variant Variation Viagra biological signal transduction cGMP cGMP kinase cGMP-Dependent Protein Kinases cardiac infarct cardiac muscle cardiomyocyte cardiovascular disorder circulatory shock coronary attack coronary infarct coronary infarction drug/agent endothelial cell derived relaxing factor guanosine 3'5'monophosphate guanylate guanylyl cyclase hearing perception heart attack heart infarct heart infarction heart ischemia heart muscle heavy metal Pb heavy metal lead heme oxygenase-1 hemeoxygenase 1 hsp70 Family human NOS2A protein iNOS enzyme inhibitor inhibitor/antagonist insight interdisciplinary approach kallidin 9 kallidin I knockout gene membrane structure men men's mitoK(ATP) mitoKATP mitochondrial mitochondrial K(ATP) channel mutant myocardial ischemia/hypoxia myocardium ischemia nitric oxide receptor nitric oxide synthase, Type II nitric oxide-sensitive guanylyl cyclase novel overexpress phosphodiesterase V phosphodiesterase-5 preconditioning prevent preventing protective effect receptor reperfusion sGC sGC protein siRNA sildenafil social role sound perception tadalafil transcription factor transfer of a gene
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL079424-04
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases > Cardiomyopathy
 
Other Information:
Fiscal Year: 2005
Project Start Date: 1 January 2004
Project End Date: 31 December 2009
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $454,221
Year Funding Organization Total Funding, $
2008 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $454,221
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL079424-04
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL079424-04
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Organization FY Funding Organization FY Total Cost
5R01HL059469-07Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2004NATIONAL HEART
$375,000
5R01HL051045-09SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2004NATIONAL HEART
$290,000
5R01HL059469-06Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2003NATIONAL HEART
$375,000
5R01HL051045-08SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2003NATIONAL HEART
$290,000
2R01HL059469-05Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2002NATIONAL HEART
$375,000
5R01HL051045-07SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2002NATIONAL HEART
$290,000
5R01HL059469-04MOLECULAR MECHANISMS OF DELAYED PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2001NATIONAL HEART
$265,698
5R01HL051045-06SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2001NATIONAL HEART
$290,000
5R01HL059469-03MOLECULAR MECHANISMS OF DELAYED PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2000NATIONAL HEART
$258,001
2R01HL051045-05SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2000NATIONAL HEART
$281,900
5R01HL059469-08Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2005NATIONAL HEART
$375,000
1R01HL079424-01CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2005NATIONAL HEART
$454,713
5R01HL059469-09Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$366,188
5R01HL079424-02CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$440,694
2R37HL051045-10Protection against Doxorubicin-Induced CardiomyopathyVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$365,640
5R01HL079424-03CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2007NATIONAL HEART
$450,503
5R37HL051045-11Protection against Doxorubicin-Induced CardiomyopathyVIRGINIA COMMONWEALTH UNIVERSITY2007NATIONAL HEART
$361,698
5R01HL079424-04CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$454,221
1R01HL093685-01Cardioprotective Signaling following Phosphodiesterase-5 InhibitionVIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$372,500
1R25HL092622-01Health Educational Research Opportunities (HERO)VIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$93,118
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL079424-04
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL079424-04
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Title Abstract Authors Year Rel
Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury. Journal of cardiovascular pharmacology. 2008 Feb 51 (2) :178-87 Natarajan, Ramesh; Salloum, Fadi N; Fisher, Bernard J; Kukreja, Rakesh C; Fowler 3rd, Alpha A 2008
Loss of myocardial ischemic postconditioning in adenosine A1 and bradykinin B2 receptors gene knockout mice. Circulation. 2008 Sep 30 118 (14 Suppl) :S32-7 Xi, Lei; Das, Anindita; Zhao, Zhi-Qing; Merino, Vanessa F; Bader, Michael; Kukreja, Rakesh C 2008
Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. American journal of physiology. Heart and circulatory physiology. 2008 Mar 294 (3) :H1398-406 Salloum, Fadi N; Abbate, Antonio; Das, Anindita; Houser, Jon-Erik; Mudrick, Colin A; Qureshi, Ian Z; Hoke, Nicholas N; Roy, Sion K; Brown, William R; Prabhakar, Shashi; Kukreja, Rakesh C 2008
Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation. 2008 May 20 117 (20) :2670-83 Abbate, Antonio; Salloum, Fadi N; Vecile, Elena; Das, Anindita; Hoke, Nicholas N; Straino, Stefania; Biondi-Zoccai, Giuseppe G L; Houser, Jon-Erik; Qureshi, Ian Z; Ownby, Evan D; Gustini, Edoardo; Biasucci, Luigi M; Severino, Anna; Capogrossi, Maurizio C; Vetrovec, George W; Crea, Filippo; Baldi, Alfonso; Kukreja, Rakesh C; Dobrina, Aldo 2008
Essential role of mitochondrial Ca2+-activated and ATP-sensitive K+ channels in sildenafil-induced late cardioprotection. Journal of molecular and cellular cardiology. 2008 Jan 44 (1) :105-13 Wang, Xiaoyin; Fisher, Patrick W; Xi, Lei; Kukreja, Rakesh C 2008
Endogenous microRNAs induced by heat-shock reduce myocardial infarction following ischemia-reperfusion in mice. FEBS letters. 2008 Dec 24 582 (30) :4137-42 Yin, Chang; Wang, Xiaoyin; Kukreja, Rakesh C 2008
Right ventricular cardiomyocyte apoptosis in patients with acute myocardial infarction of the left ventricular wall. The American journal of cardiology. 2008 Sep 15 102 (6) :658-62 Abbate, Antonio; Bussani, Rossana; Sinagra, Gianfranco; Barresi, Elena; Pivetta, Alberto; Perkan, Andrea; Hoke, Nicholas H; Salloum, Fadi N; Kontos, Michael C; Biondi-Zoccai, Giuseppe G L; Vetrovec, George W; Sabbadini, Gastone; Baldi, Feliciano; Silvestri, Furio; Kukreja, Rakesh C; Baldi, Alfonso 2008
Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. The Journal of biological chemistry. 2008 Oct 24 283 (43) :29572-85 Das, Anindita; Xi, Lei; Kukreja, Rakesh C 2008