Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1.
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.
Koneru
Srikanth
S
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health Center, Farmington, CT 06030-1110, USA.
Varma Penumathsa
Suresh
S
Thirunavukkarasu
Mahesh
M
Vidavalur
Ramesh
R
Zhan
Lijun
L
Singal
Pawan K
PK
Engelman
Richard M
RM
Das
Dipak K
DK
Maulik
Nilanjana
N
D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001160:Arterioles / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000196:embryology; D002196:Capillaries / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D009024:Morphogenesis / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000150:complications* / Q000503:physiopathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D000068677:Sildenafil Citrate