Abstract 339: Vasonatrin Peptide Attenuates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats through PKG-Mediated Inhibition of Endoplasmic Reticulum Stress
Diabetes mellitus (DM) increases morbidity/mortality of ischemic heart disease (IHD). Although atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) reduce the myocardial ischemia/reperfusion (MI/R) damage in non-diabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of ANP and CNP, confers cardioprotective effect against acute MI/R injury, especially in diabetic patients, is still unclear. This study aimed to investigate the effects of VNP on MI/R injury in diabetic rats and the involved mechanisms. The high-fat diet-fed streptozotocin (HFD-STZ) induced diabetic rats were subjected to MI/R (30 min/4 h). VNP treatment (100 µg/kg, i.v., 10 min before R) significantly improved ± LV dP/dtmax [(3242 ± 103) and -(2731 ± 79) mm Hg/s vs. (2936 ± 90) and -(2422 ± 83) mm Hg/s in DM group] and LVSP and reduced LVEDP, and reduced infarct size [(43.3 ± 3.6) % vs (53.5 ± 2.8) %], apoptosis index [(36.0 ± 2.1) % vs. (45.7 ± 3.5) %], caspase-3 activity, serum CK and LDH levels (n=8, P<0.05). Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP (n=3, P<0.05), and consequently increased the antiapoptotic protein Akt and ERK1/2 expression and phosphorylation levels (P<0.05). These effects were mimicked by 8-Br-cGMP (1 mg/kg, i.p., 20 min before R), a cGMP analogue, whereas inhibited by KT-5823 (0.5 mg/kg, i.p.), the selective inhibitor of PKG (both P<0.05). In addition, pretreated DM rats with TUDCA (50 mg/kg, i.p.), a specific inhibitor of ER stress, couldn’t further promote the VNP’s cardioprotective effect (P>0.05). In vitro study was performed using H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R, 3 h/6 h) and incubated with or without VNP (10-8mol/L). Gene knockdown of PKG1α with siRNA blunted VNP’s inhibition of ER stress and apoptosis (n=6, P<0.05), while overexpression of PKG1α resulted in significant decreased ER stress and apoptosis (n=6, P<0.01). In conclusion, VNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway. These results suggest that VNP may have potential therapeutic value for the diabetic patients with ischemic heart disease.
- © 2013 by American Heart Association, Inc.