Our innovative studies during the past 7 years have shown that potent phosphodiesterase-5 (PDE-5) inhibitors including sildenafil citrate (Viagra(R)) induce powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in various animal and cellular models. The purpose of this competing renewal application is to further demonstrate the therapeutic effect of these drugs against myocardial infarction (MI)-induced heart failure and insulin resistance in diabetic mice. We will test the following new hypotheses: 1: Modulation of cGMP with PDE-5 inhibitors and novel soluble guanylate cyclase (sGC) activator protect against myocardial infarction, apoptosis, remodeling and insulin resistance in the db/db diabetic mouse. We will determine the efficacy of short acting (sildenafil) or long acting (tadalafil) PDE-5 inhibitors and a novel sGC activator, BAY 58-2667 in protecting the diabetic heart and cardiomyocytes against myocardial infarction, apoptosis, contractile dysfunction, cardiac hypertrophy, pulmonary edema following I/R injury. 2: PDE-5 inhibitors/ sGC activator decrease oxidative stress and attenuate the expression of proinflammatory cytokines post MI in diabetic mice. 3: cGMP dependent protein kinases PKGI1 and 2 directly protect the diabetic heart through signaling mechanism involving activation of PI3K/Akt, AMPK, and inhibition of JNK and GSK- 32. These studies will be the first to demonstrate the protective effect of PDE-5 inhibitors and novel sGC activator in protection against post MI-induced heart failure in diabetic mice. We anticipate that results of these investigations will provide novel insights into expanding the utility of the cGMP preserving/generating compounds for treatment of diabetic cardiomyopathy.

Public Health Relevance

Obesity and type 2 diabetes are two of the most prevalent metabolic disorders in the world. Type II diabetes is associated with insulin resistance and increased myocardial infarction in both animal models and patients. In this proposal, we will study a new strategy for the protection of the heart and treatment of insulin resistance in Type II diabetic mice with erectile dysfunction drugs (Viagra(R) and Cialis(R)) and a novel drug BAY 58 2667 which produces cGMP - a potent muscle relaxing molecule in the body. We believe that knowledge derived from these studies will provide additional tools to the cardiologists in reducing damage of the heart following a heart attack and treatment of heart failure in diabetic patients. Moreover, our studies will help understand the molecular basis of the protection with these drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079424-08
Application #
8411180
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2005-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
8
Fiscal Year
2013
Total Cost
$416,785
Indirect Cost
$137,999
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Das, Anindita; Durrant, David; Koka, Saisudha et al. (2014) Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 289:4145-60
Shalwala, Mona; Zhu, Shu-Guang; Das, Anindita et al. (2014) Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice. PLoS One 9:e86977
Toldo, Stefano; Das, Anindita; Mezzaroma, Eleonora et al. (2014) Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice. Circ Cardiovasc Genet 7:311-20
Koka, Saisudha; Aluri, Hema S; Xi, Lei et al. (2014) Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1? signaling. Am J Physiol Heart Circ Physiol 306:H1558-68
Koka, Saisudha; Das, Anindita; Salloum, Fadi N et al. (2013) Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice. Free Radic Biol Med 60:80-8
Koka, Saisudha; Xi, Lei; Kukreja, Rakesh C (2012) Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts. Basic Res Cardiol 107:249
Salloum, Fadi N; Das, Anindita; Samidurai, Arun et al. (2012) Cinaciguat, a novel activator of soluble guanylate cyclase, protects against ischemia/reperfusion injury: role of hydrogen sulfide. Am J Physiol Heart Circ Physiol 302:H1347-54
Hoke, Nicholas N; Salloum, Fadi N; Kass, David A et al. (2012) Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. Stem Cells 30:326-35
Huizar, Jose F; Kaszala, Karoly; Potfay, Jonathan et al. (2011) Left ventricular systolic dysfunction induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol 4:543-9
Kukreja, Rakesh C; Yin, Chang; Salloum, Fadi N (2011) MicroRNAs: new players in cardiac injury and protection. Mol Pharmacol 80:558-64

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