Regulation of cardiac stress responses by pde5a

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Project Title: Regulation of cardiac stress responses by pde5a
Principal Investigators (PI): KASS DAVID ALAN
Project Number: 5R01HL089297-02
Organization: JOHNS HOPKINS UNIVERSITY
 
Project Description:
[unreadable] (provided by applicant): 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. We recently discovered that inhibitors of the phosphodiesterase PDE5a such as sildenafil, drugs widely used to treat erectile dysfunction, have potent effects on cardiac function and stress-remodeling. These and other new data supporting cardiac benefits have raised substantial interest for using these drugs to clinically treat forms of heart disease. However, remarkably little is known about how they are working particularly in the relevant setting where there disease is already established. At the primary level, inhibiting PDE5a increases the cyclic nucleotide cGMP, that can influence the heart directly, or active protein kinase G which then influences multiple proteins to modify the stress response. The cGMP/PKG system functions much like a brake, having little basal impact, but blunting cardiac stimulation by catecholamines or pathologic stress. Yet, PDE5a inhibition (PDE5a-I) appears to change cGMP levels little, while enhancing PKG activity and has effects that are quite different from other ways of enhancing cGMP/PKG (such as natriuretic peptide stimulation). New data suggests a prominent role of PDE5a-inhibition in suppressing activated G1q pathways via regulator of G-coupled signaling 2 (RGS2) and potentially canonical transient receptor potential (TRPC) channels. The mechanisms for these interactions, how they change as hypertrophic disease becomes established, and why chronic PDE5a-inhibition improves cardiac function while suppressing hypertrophy are unknown. The research in this proposal aims to provide this critical information in three aims, with studies conducted largely in mouse models, using aortic-banding pressure-overload to stimulate hypertrophy/remodeling. The first will determine how PDE5a-I acutely improves cardiac function and how this is altered by chronic hypertrophic disease. The second hones in our finding that PDE5a is post- translationally modified with chronic hypertrophy, altering activity and cellular localization less than expression, but that this impacts its stress modulation. We will identify mechanisms for this key regulation. The final aim tests the role of PKG activation and suppression of G1q-coupled signaling for both improved cardiac function and anti-hypertrophic effects in pressure-overloaded hearts. The successful completion of these studies will greatly expand our understanding of how PDE5a-I modulates normal and diseased hearts, and inform clinical trials testing such drugs for treating heart disease. RELEVENCE: Nearly 10% of the world's population develops an increase in muscle mass (hypertrophy) of their heart which increases their risk of suffering from heart disease. We discovered that sildenafil (Viagra), a drug that blocks the enzyme PDE5a and is widely used to treat erectile dysfunction, may also suppress cardiac stress-responses. This project will determine how sildenafil is working and the pathways that are involved, and how this may change in normal as opposed to diseased hearts. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]
 
Project Terms:
3'5'-cyclic ester of AMP Abbott brand of sildenafil citrate Acute Address Adenosine Cyclic 3',5'-Monophosphate Adenosine Cyclic Monophosphate Adenosine, cyclic 3',5'-(hydrogen phosphate) Adrenergic Agents Adrenergic Drugs Adrenergics Affect Antiphosphodiesterases Binding Binding (Molecular Function) Blood Pressure, High Calcium Phospholipid-Dependent Protein Kinase Calcium-Activated Phospholipid-Dependent Kinase Cardiac Cardiac Diseases Cardiac Disorders Cardiac Myocytes Cardiocyte Catecholamines Cell Communication and Signaling Cell Signaling Cells Chronic Clinical Trials Clinical Trials, Unspecified Cyclic AMP Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclic Nucleotides Data Diastolic heart failure Disease Disorder Drug usage Drugs EFRAC Ejection Fraction Endogenous Nitrate Vasodilator Endothelium-Derived Relaxing Factor Enzymes Erectile dysfunction Fluorescent Probes G-Proteins G0/G1 switch regulatory protein 8, human G0S8 protein, human GTP-Binding Proteins GTP-Regulatory Proteins Genetic Models 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) HTRPY Heart Heart Diseases Heart Hypertrophy Heart failure Heart myocyte High Prevalence Hydrolysis Hypertension Hypertrophy Intracellular Communication and Signaling Leucine Zippers Link Mammals, Mice Mediating Medication Methods Mice Models, Genetic Modification Molecular 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 Mutate Myocytes Myocytes, Cardiac NIH 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 Nucleotides, Cyclic PDE PDE2 PDE2 phosphodiesterase PKC PKG Pathologic Pathway interactions Patients Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Phosphodiesterase Antagonists Phosphodiesterase Inhibitors Phosphodiesterases Phospholipid-Sensitive Calcium-Dependent Protein Kinase Phosphoric Diester Hydrolase Inhibitors Phosphorylation Physiologic Physiological Population Post-Translational Modifications Post-Translational Protein Processing Posttranslational Modifications Pressure Pressure- physical agent Probes, Fluorescent Protein Kinase C Protein Kinase G Protein Modification Protein Modification, Post-Translational Protein Phosphorylation Protein Processing, Post-Translational Protein Processing, Posttranslational Protein/Amino Acid Biochemistry, Post-Translational Modification Proteins Proteomics Publishing RGS2 RGS2 protein, human Receptor Protein Regulation Regulator of G-Protein Signaling 2 Reporting Research Rest Rho-associated kinase Rho-kinase Risk Role Signal Transduction Signal Transduction Systems Signaling Stress Sympathins System System, LOINC Axis 4 Testing TnI Troponin I United States National Institutes of Health Vascular Hypertensive Disease Vascular Hypertensive Disorder Viagra Work adenosine 3'5'monophosphate adrenergic base biological adaptation to stress biological signal transduction cAMP cGMP cGMP kinase cGMP-Dependent Protein Kinases cardiac failure cardiac hypertrophy cardiomyocyte clinical applicability clinical application clinical investigation disease/disorder drug use drug/agent endothelial cell derived relaxing factor gene product guanosine 3'5'monophosphate heart disorder heart failure with preserved systolic function heart function human RGS2 protein hyperpiesia hyperpiesis hypertensive disease improved improved functioning inhibitor inhibitor/antagonist inhibitory troponin I interest mouse model muscle form novel pathway phospholamban phosphoric diester hydrolase pressure reaction crisis receptor regulator of G-protein signaling 2, human regulator of G-protein signalling 2, 24kDa protein, human sildenafil social role stress response stress
Project Title: Regulation of cardiac stress responses by pde5a
Principal Investigators (PI): KASS DAVID ALAN
Project Number: 5R01HL089297-02
Organization: JOHNS HOPKINS UNIVERSITY
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology, Proteins, Genes & Regulatory Networks > Cardiovascular and cerebrovascular diseases, Cell growth and division > Heart failure
 
Other Information:
Fiscal Year: 2008
Project Start Date: 14 March 2008
Project End Date: 28 February 2012
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $409,450
Year Funding Organization Total Funding, $
2009 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $409,450
Project Title: Regulation of cardiac stress responses by pde5a
Principal Investigators (PI): KASS DAVID ALAN
Project Number: 5R01HL089297-02
Organization: JOHNS HOPKINS UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Regulation of cardiac stress responses by pde5a
Principal Investigators (PI): KASS DAVID ALAN
Project Number: 5R01HL089297-02
Organization: JOHNS HOPKINS UNIVERSITY
 
Project number Project title Organization FY Funding Organization FY Total Cost
5T32HL007227-29Pathophysiology of Myocardial DiseaseJOHNS HOPKINS UNIVERSITY2004NATIONAL HEART
$440,636
5R01HL047511-11Role of Stretch to Endothelial Pulse-Perfusion ResponseJOHNS HOPKINS UNIVERSITY2004NATIONAL HEART
$367,875
1P01HL077180-01-9003CORE A--ADMINISTRATIVE COREJOHNS HOPKINS UNIVERSITY2004NATIONAL HEART
$98,821
1P01HL077180-01-9001CORE--ANIMAL COREJOHNS HOPKINS UNIVERSITY2004NATIONAL HEART
$203,090
1P01HL077180-01Pathobiology of Cardiac Dyssynchrony &ResynchronizationJOHNS HOPKINS UNIVERSITY2004NATIONAL HEART
$2,261,167
5T32HL007227-28Pathophysiology of Myocardial DiseaseJOHNS HOPKINS UNIVERSITY2003NATIONAL HEART
$745,173
5R01HL047511-10Role of Stretch to Endothelial Pulse-Perfusion ResponseJOHNS HOPKINS UNIVERSITY2003NATIONAL HEART
$367,875
2T32HL007227-26Pathophysiology of Myocardial DiseaseJOHNS HOPKINS UNIVERSITY2001NATIONAL HEART
$658,948
5T32HL007227-27Pathophysiology of Myocardial DiseaseJOHNS HOPKINS UNIVERSITY2002NATIONAL HEART
$663,508
2R01HL047511-09Role of Stretch to Endothelial Pulse-Perfusion ResponseJOHNS HOPKINS UNIVERSITY2002NATIONAL HEART
$367,875
5P50HL052307-08-9002Core--animal model and cellJOHNS HOPKINS UNIVERSITY2002NATIONAL HEART
$209,733
3P50HL052307-08S1-9002Core--animal model and cellJOHNS HOPKINS UNIVERSITY2002NATIONAL HEART
$209,733
5P50HL052307-08-0007Mechanism of neurohumoral modulation of cardiac remodelingJOHNS HOPKINS UNIVERSITY2002NATIONAL HEART
$209,733
3P50HL052307-08S1-0007Mechanism of neurohumoral modulation of cardiac remodelingJOHNS HOPKINS UNIVERSITY2002NATIONAL HEART
$209,733
5P50HL052307-07-9002Core--animal model and cellJOHNS HOPKINS UNIVERSITY2001NATIONAL HEART
$209,733
5P50HL052307-07-0007Mechanism of neurohumoral modulation of cardiac remodelingJOHNS HOPKINS UNIVERSITY2001NATIONAL HEART
$209,733
5T32HL007227-25PATHOPHYSIOLOGY OF MYOCARDIAL DISEASEJOHNS HOPKINS UNIVERSITY2000NATIONAL HEART
$499,272
5R01HL047511-08PATHOPHYSIOLOGY OF VENTRICULAR-VASCULAR INTERACTIONJOHNS HOPKINS UNIVERSITY2000NATIONAL HEART
$297,855
2P50HL052307-06-9002Core--animal model and cellJOHNS HOPKINS UNIVERSITY2000NATIONAL HEART
$209,733
2P50HL052307-06-0007Mechanism of neurohumoral modulation of cardiac remodelingJOHNS HOPKINS UNIVERSITY2000NATIONAL HEART
$209,733
Project Title: Regulation of cardiac stress responses by pde5a
Principal Investigators (PI): KASS DAVID ALAN
Project Number: 5R01HL089297-02
Organization: JOHNS HOPKINS UNIVERSITY
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Regulation of cardiac stress responses by pde5a
Principal Investigators (PI): KASS DAVID ALAN
Project Number: 5R01HL089297-02
Organization: JOHNS HOPKINS UNIVERSITY
 
Title Abstract Authors Year Rel
Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy. Circulation. 2009 Mar 10 119 (9) :1231-40 Chakir, Khalid; Daya, Samantapudi K; Aiba, Takeshi; Tunin, Richard S; Dimaano, Veronica L; Abraham, Theodore P; Jaques-Robinson, Kathryn M; Jacques, Kathryn; Lai, Edwin W; Pacak, Karel; Zhu, Wei-Zhong; Xiao, Rui-ping; Tomaselli, Gordon F; Kass, David A 2009
Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. The Journal of clinical investigation. 2009 Feb 119 (2) :408-20 Takimoto, Eiki; Koitabashi, Norimichi; Hsu, Steven; Ketner, Elizabeth A; Zhang, Manling; Nagayama, Takahiro; Bedja, Djahida; Gabrielson, Kathleen L; Blanton, Robert; Siderovski, David P; Mendelsohn, Michael E; Kass, David A 2009
Regulation of nerve growth factor in the heart: the role of the calcineurin-NFAT pathway. Journal of molecular and cellular cardiology. 2009 Apr 46 (4) :568-78 Rana, Obaida R; Saygili, Erol; Meyer, Christian; Gemein, Christopher; Kruttgen, Alexander; Andrzejewski, Michael G; Ludwig, Andreas; Schotten, Ulrich; Schwinger, Robert H G; Weber, Christian; Weis, Joachim; Mischke, Karl; Rassaf, Tienush; Kelm, Malte; Schauerte, Patrick 2009
Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway. Cardiovascular research. 2009 Feb 1 81 (2) :301-9 Hsu, Steven; Nagayama, Takahiro; Koitabashi, Norimichi; Zhang, Manling; Zhou, Liye; Bedja, Djahida; Gabrielson, Kathleen L; Molkentin, Jeffery D; Kass, David A; Takimoto, Eiki 2009