Open AccessSildenafil‐mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin‐1
Author(s) -
Koneru Srikanth,
Varma Penumathsa Suresh,
Thirunavukkarasu Mahesh,
Vidavalur Ramesh,
Zhan Lijun,
Singal Pawan K.,
Engelman Richard M,
Das Dipak K,
Maulik Nilanjana
Publication year - 2008
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00319.x
Subject(s) - sildenafil , cardioprotection , medicine , angiogenesis , vascular endothelial growth factor , neovascularization , reperfusion injury , ischemia , endocrinology , enos , pharmacology , cardiology , nitric oxide synthase , nitric oxide , vegf receptors
Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin‐1 (Ang‐1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control + IR (CIR) and sildenafil + IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2‐fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang‐1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC‐treated rats. Increased phosphorylation of Akt, eNOS and expression of anti‐apoptotic protein Bcl‐2, and thioredoxin, hemeoxygenase‐1 were observed in SC‐treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up‐regulating VEGF and Ang‐1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model.