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. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVS-B (03))
Program Officer
Liang, Isabella Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Nagiub, Mohamed; Filippone, Scott; Durrant, David et al. (2017) Long-acting PDE5 inhibitor tadalafil prevents early doxorubicin-induced left ventricle diastolic dysfunction in juvenile mice: potential role of cytoskeletal proteins. Can J Physiol Pharmacol 95:295-304
Kura, B; Yin, C; Frimmel, K et al. (2016) Changes of microRNA-1, -15b and -21 levels in irradiated rat hearts after treatment with potentially radioprotective drugs. Physiol Res 65 Suppl 1:S129-37
Das, Sayantanee; Filippone, Scott M; Williams, Denise S et al. (2016) Beet root juice protects against doxorubicin toxicity in cardiomyocytes while enhancing apoptosis in breast cancer cells. Mol Cell Biochem 421:89-101
Gill, Rabia; Kuriakose, Robin; Gertz, Zachary M et al. (2015) Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance. Mol Cell Biochem 402:41-9
Das, Anindita; Samidurai, Arun; Hoke, Nicholas N et al. (2015) Hydrogen sulfide mediates the cardioprotective effects of gene therapy with PKG-I?. Basic Res Cardiol 110:42
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

Showing the most recent 10 out of 65 publications