Cardioprotective signaling following phosphodiesterase-5 inhibition

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Project Title: Cardioprotective signaling following phosphodiesterase-5 inhibition
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL093685-02
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Description:
[unreadable] (provided by applicant): Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Nearly 200,000 patients die yearly of AMI in the US alone. AMI is caused by a sudden thrombotic obstruction to the flow in a coronary artery branch leading to myocardial ischemia (lack of oxygen) and tissue death. The most common long-term complication of AMI is the late occurrence of left ventricular dysfunction and heart failure. Limiting the extension of myocardial damage and thus preventing late occurrence of heart failure remains a current clinical challenge. Our recent innovative studies have demonstrated that potent phosphodiesterase-5 (PDE-5A) inhibitors including sildenafil citrate (Viagra) and vardenafil (Levitra) induce powerful cardioprotective effect against ischemia- reperfusioninjury (I/R) in various animal and cellular models. The purpose of this application is to further demonstrate the therapeutic effect of these drugs against myocardial infarction (MI)-induced heart failure and to develop innovative approaches for long lasting protection. We will test the following hypotheses: 1) Suppression of PDE- 5A with novel class of inhibitors or targeted gene silencing with lentiviral vector in vivo reduce post MI-induced heart failure and attenuate contractile dysfunction via inhibition of cardiomyocyte apoptosis in the heart. 2). Chronic PDE-5A inhibition suppresses oxidative/nitrosative stress by increasing the bioavailability of NO, cause inhibition of NADPH oxidase/xanthine oxidase activity, inhibit activation of redox-sensitive transcription factor, NF- thereby suppressing gene expression of proinflammatory cytokines following MI induced heart failure. 3) In vivo gene transfer of cGMP dependent protein kinases (PKGs) attenuate post MI-induced remodeling and heart failure. These studies will be the first ones to demonstrate the protective effect of PDE-5A inhibitors and novel lentiviral gene silencing approaches and associated signaling pathways in post MI-induced heart failure. We anticipate that results from these investigations will provide novel insights into expanding the utility of the PDE-5A inhibitors for other cardiovascular indications in addition to their current clinical use for treatment of erectile dysfunction and pulmonary hypertension. (PIDEPUBLIC HEALTH RELEVANCE: Acute myocardial infarction (AMI) continues to be a major cause of morbidity and mortality worldwide. AMI is caused by a sudden obstruction to the flow in a coronary artery branch leading to myocardial ischemia (lack of oxygen) and tissue death. The long-term complication of AMI is the late occurrence of left ventricular dysfunction (`weakening of the heart') and heart failure. In this proposal, we will study the effect of erectile dysfunction drugs (Viagra, Levitra and Cialis) and novel gene silencing approaches to limit the damage of the heart following AMI. We believe that knowledge derived from these studies will provide additional tools to the cardiologists for treatment of heart failure with clinically approved erectile dysfunction drugs. In addition, our investigations will open up another innovative gene silencing option to treat AMI and ventricular remodeling in patients. [unreadable] [unreadable] [unreadable]
 
Project Terms:
1-(((3-(3,4-dihydro-5-methyl)-4-oxo-7-propylimidazo(5,1-f)-as-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethylpiperazine 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 Abbott brand of sildenafil citrate Abbreviations Active Oxygen Acute myocardial infarct Acute myocardial infarction Adenosine Adverse effects Animals Anterior Antioxidants Apoptosis Apoptosis Pathway Apoptotic Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Attenuated Bayer brand of vardenafil hydrochloride Bioavailability Biologic Availability Biological Availability Body Tissues Bradykinin Caliber Cardiac Failure Congestive Cardiac Myocytes Cardiac Remodeling, Ventricular Cardiac artery Cardiac infarction Cardiocyte Cardiomyopathies Cardiovascular Cardiovascular Body System Cardiovascular system Cardiovascular system (all sites) Cell Communication and Signaling Cell Culture Techniques Cell Death Cell Death, Programmed Cell Signaling Cell model Cell/Tissue, Immunohistochemistry Cellular model Cessation of life Chemistry Chronic Cialis Citrates Clinical Clinical Trials Clinical Trials, Unspecified Closure by Ligation Complication Congestive Heart Failure Coronary artery Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cytokine Gene DNA Molecular Biology Death Deoxyguanylate Cyclase Diameter Dose Drugs Dysfunction EC 1.1.3.22 EC 2.7 EC 2.7.2- Endogenous Nitrate Vasodilator Endothelium-Derived Relaxing Factor Enzymes Erectile dysfunction Extracellular Signal-Regulated Kinases Functional disorder G-Proteins GTP pyrophosphate-lyase (cyclizing) GTP-Binding Proteins GTP-Regulatory Proteins Gene Expression Gene Inactivation Gene Silencing Gene Transfer Generations Genes Glycogen Synthase Kinases 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 Heart Heart Decompensation Heart Failure, Congestive Heart Hypertrophy Heart artery Heart failure Heart myocyte Human Human, General Hypertension, Pulmonary Hypoxanthine Dehydrogenase Hypoxanthine Oxidase Hypoxanthine-Xanthine Oxidase IHC Immunohistochemistry Immunohistochemistry Staining Method In Situ Inflammatory Injury Inosinate Cyclase Inositide Phospholipids Inositol Phosphoglycerides Inositol Phospholipids Intracellular Communication and Signaling Investigation Ischemia Ischemic Heart Ischemic Heart Disease Ischemic Preconditioning Ischemic myocardium K element Kinases Knowledge Lead Left Left Ventricular Dysfunction Lentiviral Vector Lentivirus Vector Levitra Ligation Lilly brand of tadalafil MAP kinase MAPK MMC Mammals, Mice Mammals, Rabbits Man (Taxonomy) Man, Modern Mediating Mediator Mediator of Activation Mediator of activation protein Medication Methods and Techniques Methods, Other Mice Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Biology Mononitrogen Monoxide Morbidity Morbidity - disease rate Mortality Mortality Vital Statistics Murine Mus Muscle Cells, Cardiac Muscle Cells, Heart Mycocardium Disease Myocardial Myocardial Diseases Myocardial Disorder Myocardial Infarct Myocardial Infarction Myocardial Ischemia Myocardial Remodeling, Ventricular Myocardiopathies Myocytes, Cardiac NADPH Oxidase Nitric Oxide Nitric Oxide, Endothelium-Derived Nitrogen Monoxide Nitrogen Protoxide Nitrogen oxide Nuclear O element O2 element Obstruction Oligo Oligonucleotides Organ System, Cardiovascular Oryctolagus cuniculus Oxidases Oxidation-Reduction Oxidative Stress Oxygen Oxygen Radicals PDE PDE 5 enzyme PKG Patients Pb element Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Phosphatidyl Inositol Phosphatidylinositols Phosphodiesterases Phosphoinositides Phosphorylation Phosphotransferases Physiologic Availability Physiology Physiopathology Potassium Preconditionings, Ischemic Pro-Oxidants Protein Kinase G Protein Phosphorylation PtdIns Pulmonary Edema Pulmonary Hypertension Purine-Xanthine Oxidase RNA, Small Interfering Rabbit, Domestic Rabbits Reactive Oxygen Species Redox Reperfusion Therapy Role Science of Chemistry Signal Pathway Signal Transduction Signal Transduction Pathway Signal Transduction Systems Signaling Sildenafil citrate Silenafil Citrate Small Interfering RNA Techniques Testing Therapeutic Effect Thick Thickness Tissues Transphosphorylases Treatment Side Effects Vascular, Heart Ventricle Remodeling Ventricular Ventricular Dysfunction, Left Ventricular Remodeling Viagra Xanthine Oxidase Xanthine[{..}]oxygen oxidoreductase anti-oxidant attenuation bioavailability of drug biological signal transduction cGMP cGMP kinase cGMP-Dependent Protein Kinases cardiac failure cardiac hypertrophy cardiac infarct cardiomyocyte circulatory system clinical investigation clinical relevance clinically relevant coronary attack coronary infarct coronary infarction cyclosporin A-SPTP cyclosporin A-sensitive pereability transition pore cytokine drug/agent endothelial cell derived relaxing factor guanosine 3'5'monophosphate guanylyl cyclase heart attack heart infarct heart infarction heart ischemia heavy metal Pb heavy metal lead in vivo inhibitor inhibitor/antagonist innovate innovation innovative insight interdisciplinary approach kallidin 9 kallidin I lung edema men men's mitoK(ATP) mitoKATP mitochondrial mitochondrial K(ATP) channel mitochondrial megachannel mitochondrial permeability transition pore myocardial ischemia/hypoxia myocardial remodeling myocardium disorder myocardium ischemia necrocytosis nitrosative stress novel oxidation reduction reaction pathophysiology percutaneous coronary intervention phosphodiesterase V phosphodiesterase-5 phosphoric diester hydrolase preconditioning prevent preventing protective effect receptor-mediated signaling reperfusion shRNA short hairpin RNA siRNA side effect sildenafil small hairpin RNA social role tadalafil therapy adverse effect tool transcription factor transfer of a gene treatment adverse effect vardenafil
Project Title: Cardioprotective signaling following phosphodiesterase-5 inhibition
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL093685-02
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases > Heart failure, Diseases of arteries, arterioles and capillaries > Aortic aneurysm
 
Other Information:
Fiscal Year: 2008
Project Start Date: 14 July 2008
Project End Date: 30 June 2013
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $373,750
Year Funding Organization Total Funding, $
2009 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $373,750
Project Title: Cardioprotective signaling following phosphodiesterase-5 inhibition
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL093685-02
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Cardioprotective signaling following phosphodiesterase-5 inhibition
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL093685-02
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 signaling following phosphodiesterase-5 inhibition
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL093685-02
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Cardioprotective signaling following phosphodiesterase-5 inhibition
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R01HL093685-02
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Title Abstract Authors Year Rel
A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circulation research. 2009 Mar 13 104 (5) :572-5 Yin, Chang; Salloum, Fadi N; Kukreja, Rakesh C 2009
cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium. The Journal of pharmacology and experimental therapeutics. 2009 Sep 330 (3) :884-91 Vandeput, Fabrice; Krall, Judith; Ockaili, Ramzi; Salloum, Fadi N; Florio, Vincent; Corbin, Jackie D; Francis, Sharron H; Kukreja, Rakesh C; Movsesian, Matthew A 2009
ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice. American journal of physiology. Heart and circulatory physiology. 2009 May 296 (5) :H1236-43 Das, Anindita; Salloum, Fadi N; Xi, Lei; Rao, Yuan J; Kukreja, Rakesh C 2009