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: 1R01HL079424-01
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:
cGMP dependent protein kinase drug screening /evaluation laboratory mouse myocardial ischemia /hypoxia tissue /cell culture
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 1R01HL079424-01
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: $454,713
Year Funding Organization Total Funding, $
2005 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $454,713
Project Title: Cardioprotective effects of pde-5 inhibitors
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 1R01HL079424-01
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: 1R01HL079424-01
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: 1R01HL079424-01
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: 1R01HL079424-01
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Title Abstract Authors Year Rel
Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. The Journal of biological chemistry. 2005 Apr 1 280 (13) :12944-55 Das, Anindita; Xi, Lei; Kukreja, Rakesh C 2005
Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. Vascular pharmacology. 2005 Apr-May 42 (5-6) :219-32 Kukreja, Rakesh C; Salloum, Fadi; Das, Anindita; Ockaili, Ramzi; Yin, Chang; Bremer, Yvonne A; Fisher, Patrick W; Wittkamp, Michael; Hawkins, John; Chou, Eric; Kukreja, Amit K; Wang, Xiaoyin; Marwaha, Vijay R; Xi, Lei 2005
Silencing heat shock factor 1 by small interfering RNA abrogates heat shock-induced cardioprotection against ischemia-reperfusion injury in mice. Journal of molecular and cellular cardiology. 2005 Oct 39 (4) :681-9 Yin, Chang; Xi, Lei; Wang, Xiaoyin; Eapen, Mareen; Kukreja, Rakesh C 2005