Diabetes abrogates the cardioprotective effects of ischemic postconditioning by impairing AdipoR1/Caveolin-3/STAT3 signaling

Abstract

INTRODUCTION: Ischemic postconditioning (IPo) protects against myocardial ischemia reperfusion (MI/R) injury by activating mitochondrial signal transducer and activator of transcription 3 (mitoSTAT3) through adiponectin (APN) in non-diabetes, but losses its effectiveness in diabetes whose cardiac APN is reduced. We postulated that malfunction of APN is the key mechanism whereby IPo losses cardioprotection in diabetes. METHODS AND RESULTS: Four-week (4w) or eight-week (8w) streptozotocin-induced diabetic rats were treated with APN adenovirus (tail vein injection, 1*109 pfu) 1-week before inducing MI/R (30 minutes of left coronary artery ligation followed by 2 hours of reperfusion) with or without IPo (3 cycles of 10s of ischemia and 10s of reperfusion, n=6 per group). At the end of reperfusion, myocardial injury was more severe in both 4w and 8w diabetic rats evidenced as increased infarct size than age-matched control (43.4±3.3 in 4w diabetic vs. 30.6±2.2 in control, 55.4±2.0 in 8w diabetic vs. 38.0±1.9 in control, all P<0.05) concomitant with increased plasma CK-MB release and worse cardiac function (lower dP/dtmax and ejection fraction), and more severely impaired mitochondrial function (decrease in complex I, II+III, and IV activities), more severe reduction of activated mitoSTAT3 and colocolization of APN receptor-1(AdipoR1) and caveolin-3(Cav3), a molecule essential for APN signaling. These changes cannot be reversed by IPo alone in both 4w and 8w diabetic rats, while IPo in combination with APN significantly attenuated all the abovementioned changes in 4w diabetic but not in 8w diabetic rats whose baseline and post-ischemic cardiac AdipoR1 and Cav3 expression were more severely reduced than that in 4 w diabetic rats. The protective effects of joint IPo and APN treatment in 4w diabetes were abolished by inhibition of STAT3 irrespectiove of IPo and APN induced enhancement of AdipoR1 and Cav3 expression and colocalization. CONCLUSION: IPo loses cardioprotection in diabetes due to reduced APN and impaired AdipoR1/Cav3 signaling. APN supplementation by activating mitoSTAT3 restores IPo cardioprotection in 4w diabetic where AdipoR1 and Cav3 are functionally interactive, but not in 8w diabetic rats whose AdipoR1/Cav3 signaling impaired.