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| Project Title: | Cardioprotective effects of pde-5 inhibitors | |
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
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| Project Number: | 5R01HL079424-02 | |
| 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: | 5R01HL079424-02 | |
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |
| Project Categories: | ||
|---|---|---|
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• Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases > Cardiomyopathy |
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| 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: | $440,694 | |
| Year | Funding Organization | Total Funding, $ |
|---|---|---|
| 2006 | NATIONAL HEART, LUNG, AND BLOOD INSTITUTE | $440,694 |
| Project Title: | Cardioprotective effects of pde-5 inhibitors | ||
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
||
| Project Number: | 5R01HL079424-02 | ||
| 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: | 5R01HL079424-02 | |
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |
| Project Title: | Cardioprotective effects of pde-5 inhibitors | ||
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
||
| Project Number: | 5R01HL079424-02 | ||
| 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: | 5R01HL079424-02 | |||
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |||
| Title | Abstract | Authors | Year | Rel |
|---|---|---|---|---|
| Mechanism of reactive oxygen species generation after opening of mitochondrial KATP channels. | American journal of physiology. Heart and circulatory physiology. 2006 Nov 291 (5) :H2041-3 | Kukreja, Rakesh C | 2006 |
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| Synergistic effects of atorvastatin and sildenafil in cardioprotection--role of NO. | Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. 2006 Feb 20 (1) :5-8 | Kukreja, Rakesh C | 2006 |
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| Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. | Journal of molecular and cellular cardiology.. 2006 Aug 41 (2) :256-64 | Khan, Shakil; Salloum, Fadi; Das, Anindita; Xi, Lei; Vetrovec, George W; Kukreja, Rakesh C | 2006 |
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| Genetic deletion of fas receptors or Fas ligands does not reduce infarct size after acute global ischemia-reperfusion in isolated mouse heart. | Cell biochemistry and biophysics.. 2006 44 (1) :111-7 | Tekin, Demet; Xi, Lei; Kukreja, Rakesh C | 2006 |
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| Hypercholesterolemia enhances tolerance to lethal systemic hypoxia in middle-aged mice: possible role of VEGF downregulation in brain. | Molecular and cellular biochemistry. 2006 Oct 291 (1-2) :205-11 | Xi, Lei; Ghosh, Shobha; Wang, Xiaoyin; Das, Anindita; Anderson, Frank P; Kukreja, Rakesh C | 2006 |
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| Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits. | Journal of molecular and cellular cardiology.. 2006 Mar 40 (3) :405-11 | Salloum, Fadi N; Ockaili, Ramzi A; Wittkamp, Michael; Marwaha, Vijay R; Kukreja, Rakesh C | 2006 |
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| Cyclic GMP-dependent protein kinase Ialpha attenuates necrosis and apoptosis following ischemia/reoxygenation in adult cardiomyocyte. | The Journal of biological chemistry. 2006 Dec 15 281 (50) :38644-52 | Das, Anindita; Smolenski, Albert; Lohmann, Suzanne M; Kukreja, Rakesh C | 2006 |
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| Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. | Circulation research.. 2006 Jan 6 98 (1) :133-40 | Natarajan, Ramesh; Salloum, Fadi N; Fisher, Bernard J; Kukreja, Rakesh C; Fowler 3rd, Alpha A | 2006 |
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