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| Project Title: | Protection against doxorubicin-induced cardiomyopathy | |
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
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| Project Number: | 5R37HL051045-11 | |
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |
| Project Description: | ||
|---|---|---|
| Doxorubicin (DOX) is a potent and effective chemotherapeutic agent belonging to the anthracycline class of antibiotics. It is used frequently in the treatment of many hematologic and solid tumor malignancies. Despite its clinical efficacy, DOX's use is often limited by its potential for causing dose-dependent cardiotoxicity. Our recent studies have shown that potent phosphodiesterase-5A (PDE-5A) inhibitor, sildenafil citrate (Viagra), which is known to enhance erectile function in men, induces powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in the rabbit and mouse hearts. The purpose of this application is to show the effect of class of novel PDE-5A inhibitors on DOX-induced cardiomyocyte apoptosis and to understand signaling pathways which lead to a long lasting cardioprotection. We will test the following hypotheses: 1) Suppression of PDE-5A with novel class of inhibitors attenuate DOX-induced cardiotoxicity and contractile dysfunction via inhibition of cardiomyocyte apoptosis in the heart. We will also determine the effect of PDE-5 inhibitors on anti-tumor properties of DOX. 2). PDE-5A inhibitor(s) trigger signaling mechanisms involving activation of transcription factor, GATA-4, which leads to enhanced expression of Bcl-2 and attenuate cardiomyocytes apoptosis following DOX-treatment 3) PDE-5A inhibitors stimulate guanylate cyclase and elevate cGMP causing activation of protein kinase G (PKG) leading to attenuation of DOX-induced cardiotoxicity. 4) PDE-5A inhibitors drive the expression of heat shock proteins through gene transcription and activation of heat shock transcription factor-1 which may result in reduction of DOX-induced cardiotoxicity in the heart. This study will be the first one to demonstrate the protective effect of PDE-5A inhibitors in DOX-induced cardiotoxicity in the heart at cellular and sub-cellular level. These studies will also provide valuable information leading to eventual clinical trials in humans receiving DOX-chemotherapy for hematologic and/or oncologic neoplasms. | ||
| Project Terms: | ||
| BCL2 gene /protein cGMP dependent protein kinase drug adverse effect laboratory mouse myocardial ischemia /hypoxia tissue /cell culture | ||
| Project Title: | Protection against doxorubicin-induced cardiomyopathy | |
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
|
| Project Number: | 5R37HL051045-11 | |
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |
| Project Categories: | ||
|---|---|---|
|
• Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases > Cardiomyopathy |
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| Other Information: | ||
| Fiscal Year: | 1995 | |
| Project Start Date: | 1 August 1995 | |
| Project End Date: | 31 December 2010 | Administering Institute Or Center: | HL |
| Project Funding Information: | ||
| Total Funding: | $361,698 | |
| Year | Funding Organization | Total Funding, $ |
|---|---|---|
| 2007 | NATIONAL HEART, LUNG, AND BLOOD INSTITUTE | $361,698 |
| Project Title: | Protection against doxorubicin-induced cardiomyopathy | ||
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
||
| Project Number: | 5R37HL051045-11 | ||
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | ||
| Project_number | Title | Year | FY Total Cost |
|---|---|---|---|
| There are no results for this project in database. | |||
| Project Title: | Protection against doxorubicin-induced cardiomyopathy | |
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
|
| Project Number: | 5R37HL051045-11 | |
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |
| Project Title: | Protection against doxorubicin-induced cardiomyopathy | ||
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
||
| Project Number: | 5R37HL051045-11 | ||
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | ||
| Project number | Project title | Principal investigator | |
|---|---|---|---|
| There are no any related projects. | |||
| Project Title: | Protection against doxorubicin-induced cardiomyopathy | |||
| Principal Investigators (PI): |
KUKREJA RAKESH C
|
|||
| Project Number: | 5R37HL051045-11 | |||
| Organization: | VIRGINIA COMMONWEALTH UNIVERSITY | |||
| Title | Abstract | Authors | Year | Rel |
|---|---|---|---|---|
| Adenosine A(1) receptor mediates delayed cardioprotective effect of sildenafil in mouse. | Journal of molecular and cellular cardiology. 2007 Nov 43 (5) :545-51 | Salloum, Fadi N; Das, Anindita; Thomas, Christopher S; Yin, Chang; Kukreja, Rakesh C | 2007 |
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| eNOS phosphorylation: a pivotal molecular switch in vasodilation and cardioprotection? | Journal of molecular and cellular cardiology. 2007 Feb 42 (2) :280-2 | Kukreja, Rakesh C; Xi, Lei | 2007 |
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| Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. | Journal of molecular and cellular cardiology. 2007 Feb 42 (2) :453-8 | Salloum, Fadi N; Takenoshita, Yuko; Ockaili, Ramzi A; Daoud, Vladimir P; Chou, Eric; Yoshida, Kazu-ichi; Kukreja, Rakesh C | 2007 |
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| Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium. | American journal of physiology. Heart and circulatory physiology. 2007 Sep 293 (3) :H1571-80 | Natarajan, Ramesh; Salloum, Fadi N; Fisher, Bernard J; Ownby, Evan D; Kukreja, Rakesh C; Fowler 3rd, Alpha A | 2007 |
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| Cardiovascular protection with sildenafil following chronic inhibition of nitric oxide synthase. | British journal of pharmacology. 2007 Mar 150 (5) :538-40 | Kukreja, R C | 2007 |
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