Role and mechanism of adiponectin in ischemic postconditioning cardioprotection against myocardial ischemia reperfusion injury in type 1 diabetes

Abstract

Myocardial infarction remains the major perioperative complication that is associated with significant morbidity and mortality in patients with diabetes. Ischemic postconditioning (IPo) protects against myocardial ischemia reperfusion (IR) injury by activating signal transducer and activator of transcription 3(STAT3) in non-diabetes, but losses its effectiveness in diabetes, a pathology that is associated with reduction and/or malfunction of the cardioprotective molecule, adiponectin (APN). This thesis reports the results of three studies designed to determine the role of APN in IPo cardioprotection and its interplay with STAT3, and to identify the mechanism by which adiponectin interacts with cardiac STAT3 in the context of IPo in non-diabetic and diabetic subjects.

In the first study, by applying different durations of ischemia and reperfusion in an in vivo ischemia reperfusion model, we explored whether or not hearts from diabetes is more susceptible to myocardial IR injury. We showed that hearts from diabetes, even at the early stage of the disease, is more vulnerable to myocardial IR injury than hearts from non-diabetic subjects. Furthermore, we showed that the severity of the post-ischemic myocardial injury of the diabetic hearts depended more on the duration of ischemia than that of reperfusion.

In the second study, we investigated the mechanism underlies the cardioprotective effects of APN in attenuating diabetic cardiomyopathy, with a special focus on the role of APN’s anti-oxidative effects in this process. We showed that APN, through concomitantly activating Nrf2 and Brg1, activated myocardial heme oxygenase-1(HO-1), which played critical roles in attenuating cardiac hypertrophy and cardiac dysfunction in streptozotocin-induced diabetic rats. Consistently, in cultured adult rat cardiomyocytes and cardiac H9C2 cells, administration of APN prevented high glucose(HG)-induced reduction of HO-1, Brg1, and nuclear Nrf2 protein expression and attenuated HG-induced elevations of lipid peroxidation, cardiomyocyte size, and apoptosis. However, these cardioprotective effects of APN were cancelled by either Nrf2, Brg1, or HO-1 inhibition/genes knockdown.

Furthermore, we found that IPo increased post-ischemic cardiomyocyte-derived APN, activated mitochondrial STAT3 (mitoSTAT3), improved mitochondrial function, reduced myocardial oxidative stress, and ultimately attenuated myocardial IR injury, in wild-type but not in APN knockout (〖Adipo〗^(-/-)) mice. IPo-induced protection was lost in cardiomyocytes isolated from 〖Adipo〗^(-/-)mice but restored by recombinant APN, while this APN beneficial effect was abolished by either specific STAT3 or APN receptor1 (AdipoR1) gene knockdown, or caveolin-3 (Cav3) disruption. APN activated STAT3 and restored IPo cardioprotection in 4-week diabetic where AdipoR1 and Cav3 were functionally interactive, but not in 8-week diabetic rats whose cardiac Cav3 was severely reduced and AdipoR1/Cav3 signaling impaired.

It is concluded that IPo activates mitoSTAT3 through APN/AdipoR1/Cav3 pathway to confer cardioprotection, while in diabetes, IPo loses cardioprotection due to impaired APN/AdipoR1/Cav3 signaling.

It is hoped that studies described in this thesis have enhanced the knowledge concerning the role of APN in the cardioprotection of IPo against myocardial IR injury and its importance for IPo to confer cardioprotection in diabetes. Findings observed in our studies may facilitate the development of novel and effective therapies for the treatment of ischemic heart disease which is common in patients with diabetes.