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.
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.
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|Das, Anindita; Durrant, David; Salloum, Fadi N et al. (2015) PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol Ther 147:12-21|
|Salloum, Fadi N; Sturz, Gregory R; Yin, Chang et al. (2015) Beetroot juice reduces infarct size and improves cardiac function following ischemia-reperfusion injury: Possible involvement of endogenous H2S. Exp Biol Med (Maywood) 240:669-81|
|Das, Anindita; Salloum, Fadi N; Filippone, Scott M et al. (2015) Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling. Basic Res Cardiol 110:31|
|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|
|Salloum, Fadi N; Chau, Vinh Q; Hoke, Nicholas N et al. (2014) Tadalafil prevents acute heart failure with reduced ejection fraction in mice. Cardiovasc Drugs Ther 28:493-500|
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