Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy

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Project Title: Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy
Principal Investigators (PI): TAKIMOTO EIKI
Project Number: 3R01HL093432-01A1S1
Organization: JOHNS HOPKINS UNIVERSITY
 
Project Description:
Cardiac hypertrophic remodeling underlies a large component of the morbidity and mortality of heart disease. It affects nearly 10% of the world's population given the high prevalence of hypertension and hypertrophy that evolves with it. Cyclic guanosine-3', 5'-monophosphate (cGMP) is an intracellular second messenger which controls diverse cell physiology. Accumulating evidence shows that enhanced synthesis of cGMP by nitric oxide or natriuretic peptides negatively regulate cardiac hypertrophy development. We recently found that blocking cGMP degradation with phospho- diesterase5A (PDE5A) inhibitor have potent anti-hypertrophic and anti-remodeling effects. One major downstream mediator of cGMP is cGMP-dependent protein kinase (cGK). It remains unclear how cGMP and its downstream cGK regulate intra-cellular signaling network, resulting in such physiological impact on the heart. PDE5A inhibitors are currently widely used to treat erectile dysfunction and pulmonary hypertension. Reports from us and others supporting cardiac benefits from cGMP enhancement by PDE5A inhibitors have raised substantial interest for these drugs in treatment of human heart disease. To clarify the underlying mechanism of this signaling takes on more prominence now that the NIH is expected to initiate a clinical trial of PDE5A inhibitor in heart failure patients. Our preliminary data suggest that cGMP- activated cGK type I1 (cGKI1) targets two different molecules to exert beneficial effects over stressed or diseased heart, depending on its intracellular location at different stages of cardiac remodeling. cGKI1 blunts Gq signaling by activating its inhibitory protein named regulator of G-protein coupled signaling 2 (RGS2) at the sarcolemmal membrane in the early phase of hypertrophy development, whereas in the late phase (failure), it up-regulates PGC-11 (peroxisome proliferators-activated receptor 3 coactivator 1-1), a master regulator of mitochondrial biogenesis and function possibly in the nucleus. The research in this proposal aims to provide critical information on the mechanisms of this regulation in two aims by utilizing animals deficient in RGS2 (conventional and inducible conditional) and animals harboring mutant cGKI1 in which critical protein- protein interaction site (leucine zipper motif) is disrupted. The first aim will examine the cardio- protective mechanism of GKI1 in the early hypertrophy development phase. The second aim will examine the role and the mechanism of PGC-11 regulation by cGKI1, and its impact on mitochondrial biogenesis/ function in the late phase of cardiac failure. The successful completion of these studies will greatly expand our understanding of the role for cGMP signaling in diseased hearts, and inform clinical trials testing cGMP signaling-enhancing drugs such as PDE5A inhibitors for treating heart disease. PUBLIC HEALTH RELEVANCE: Nearly 10% of the world's population develops cardiac hypertrophy which increases their risk of suffering from heart disease, and sudden death. We discovered that cardiac hypertrophy/ remodeling is ameliorated by enhancing intrinsic cGMP pathway with sildenafil (Viagra), the drug currently widely used for treating erectile dysfunction. This project will clarify the underlying mechanisms for this beneficial impact from enhanced cGMP signaling pathway in the heart, focusing on a major downstream molecule and its interaction with other key regulators.
 
Project Terms:
ATP biosynthesis (oxidative) ATP-protein phosphotransferase Abbott brand of sildenafil citrate Address Affect Agonist Animals Binding Binding (Molecular Function) Biogenesis Blood Pressure, High Cardiac Cardiac Diseases Cardiac Disorders Cardiac Myocytes Cardiocyte Cell Communication and Signaling Cell Function Cell Nucleus Cell Process Cell Signaling Cell physiology Cellular Function Cellular Physiology Cellular Process Clinical Trials Clinical Trials, Unspecified Compensation Coupled Coupling Cyclic GMP Cyclic GMP-Dependent Protein Kinases D-Glucose Data Death, Sudden Defense Mechanisms Deoxyguanylate Cyclase Development Dextrose Disease Disorder Down-Regulation Down-Regulation (Physiology) Downregulation Drugs Dysfunction EC 2.7 Endogenous Nitrate Vasodilator Endothelium-Derived Relaxing Factor Energy Expenditure Energy Metabolism Erectile dysfunction FLR Failure (biologic function) Family Financial compensation Functional disorder G-Proteins G0/G1 switch regulatory protein 8, human G0S8 protein, human GTP Phosphohydrolases GTP pyrophosphate-lyase (cyclizing) GTP-Binding Proteins GTP-Regulatory Proteins GTPases Genetic Genetic Models Glucose 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 Triphosphate Phosphohydrolases Guanosine, cyclic 3',5'-(hydrogen phosphate) Guanosinetriphosphatases Guanyl Cyclase Guanylate Cyclase HTRPY Heart Heart Diseases Heart Hypertrophy Heart failure Heart myocyte High Prevalence Human Human, General Hypertension Hypertension, Pulmonary Hypertrophy In Vitro Inosinate Cyclase Intermediary Metabolism Intracellular Communication and Signaling Intracellular Second Messenger Intracellular Second Messengers Kinases Knock-out Knockout Leucine Zippers Location METBL Mammals, Mice Man (Taxonomy) Man, Modern Mediator Mediator of Activation Mediator of activation protein Medication Membrane Metabolic Processes Metabolism Mice Mitochondria Models, Genetic Molecular Interaction Mononitrogen Monoxide Morbidity Morbidity - disease rate Mortality Mortality Vital Statistics Murine Mus Muscle Cells Muscle Cells, Cardiac Muscle Cells, Heart Muscle Cells, Mature Myocardial Myocytes Myocytes, Cardiac NIH Names National Institutes of Health National Institutes of Health (U.S.) Natriuretic Peptide Hormones Natriuretic Peptides Nitric Oxide Nitric Oxide, Endothelium-Derived Nitrogen Monoxide Nitrogen Protoxide Nitrogen oxide Nuclear Nucleus Origin of Life Oxidative Phosphorylation Oxidative Phosphorylation Pathway PDE PKG PPAR Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Phase Phosphodiesterases Phosphotransferases Physiologic Physiological Physiopathology Play Population Pressure Pressure- physical agent Protein Binding Protein Kinase Protein Kinase G Proteins Pulmonary Hypertension RGS2 RGS2 protein, human Recruitment Activity Regulation Regulator of G-Protein Signaling 2 Reporting Research Risk Role Second Messenger Systems Second Messengers Second Messengers of Signal Transduction Signal Pathway Signal Transduction Signal Transduction Systems Signaling Site Staging Stress Study models Subcellular Process Sudden Death Testing Time Transphosphorylases United States National Institutes of Health Up-Regulation Up-Regulation (Physiology) Upregulation Vascular Hypertensive Disease Vascular Hypertensive Disorder Viagra base biological adaptation to stress biological signal transduction cGMP cGMP kinase cGMP-Dependent Protein Kinases cardiac failure cardiac hypertrophy cardiac metabolism cardiomyocyte clinical investigation constriction disease/disorder drug/agent endothelial cell derived relaxing factor energy balance failure fatty acid oxidation gene product glycogen synthase a kinase guanosine 3'5'monophosphate guanosinetriphosphatase guanylyl cyclase heart disorder heart metabolism human RGS2 protein hydroxyalkyl protein kinase hyperpiesia hyperpiesis hypertensive disease improved in vivo inhibitor inhibitor/antagonist interest member membrane structure mitochondrial mouse model mutant pathophysiology pathway phosphoric diester hydrolase phosphorylase b kinase kinase pressure protein protein interaction psychological defense mechanism public health relevance reaction crisis recruit regulator of G-protein signaling 2, human regulator of G-protein signalling 2, 24kDa protein, human response sildenafil social role stress response stress
Project Title: Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy
Principal Investigators (PI): TAKIMOTO EIKI
Project Number: 3R01HL093432-01A1S1
Organization: JOHNS HOPKINS UNIVERSITY
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology, Metabolism & Nutrition > Cardiovascular and cerebrovascular diseases, Calcium metabolism > Heart failure
 
Other Information:
Fiscal Year: 2009
Project Start Date: 15 July 2009
Project End Date: 30 June 2011
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $313,912
Year Funding Organization Total Funding, $
2009 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $313,912
Project Title: Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy
Principal Investigators (PI): TAKIMOTO EIKI
Project Number: 3R01HL093432-01A1S1
Organization: JOHNS HOPKINS UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy
Principal Investigators (PI): TAKIMOTO EIKI
Project Number: 3R01HL093432-01A1S1
Organization: JOHNS HOPKINS UNIVERSITY
 
Project number Project title Organization FY Funding Organization FY Total Cost
1R01HL093432-01A1Regulation and function of cGMP dependent protein kinase in cardiac hypertrophyJOHNS HOPKINS UNIVERSITY2009NATIONAL HEART
$410,000
3R01HL093432-01A1S1Regulation and function of cGMP dependent protein kinase in cardiac hypertrophyJOHNS HOPKINS UNIVERSITY2009NATIONAL HEART
$313,912
5R01HL093432-03Regulation and function of cGMP dependent protein kinase in cardiac hypertrophyJOHNS HOPKINS UNIVERSITY2011NATIONAL HEART
$410,000
5R01HL093432-02Regulation and function of cGMP dependent protein kinase in cardiac hypertrophyJOHNS HOPKINS UNIVERSITY2010NATIONAL HEART
$410,000
Project Title: Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy
Principal Investigators (PI): TAKIMOTO EIKI
Project Number: 3R01HL093432-01A1S1
Organization: JOHNS HOPKINS UNIVERSITY
 
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Project Title: Regulation and function of cgmp dependent protein kinase in cardiac hypertrophy
Principal Investigators (PI): TAKIMOTO EIKI
Project Number: 3R01HL093432-01A1S1
Organization: JOHNS HOPKINS UNIVERSITY
 
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