Propofol confers cardioprotection via HO-1 dependent STAT3 activation in normal rats but via adiponectin dependent STAT3 activation in type 1 diabetic rats

Abstract

INTRODUCTION: Ischemic heart disease leads to an exceedingly high mortality, especially in patients with diabetes. Propofol, an anesthetic with antioxidant and peroxynitrite scavenging properties, when given during early reperfusion (propofol postconditioning, PPC) attenuates myocardial ischemia/reperfusion injury (IRI)1 . However, the underlying mechanism of PPC cardioprotection is unclear. Moreover, diabetic heart is more vulnerable to IRI and not sensitive to postconditioning (IPost) cardioprotection with unclear mechanism2 . The aims of this study were to examine whether PPC cardioprotection is mainly achieved via scavenging peroxynitirite, and whether PPC is effective in diabetes. Further, we aimed to study the role of heme oxygenase-1 (HO-1) and signal transducer and activator of transcription 3 (STAT3), key proteins in IPost cardioprotection in PPC, and their association with adiponectin (APN), a molecule with anti-diabetic property.

METHODS: Control (C) and streptozotocin induced diabetic (D) adult Sprague-Dawley rats were subjected myocardial IRI induced by 30min coronary occlusion followed by 2 hours of reperfusion, without or with PPC [perfused with propofol, 2mg/ kg body weight], FeTPPS (peroxynitrite scavenger, 10mg/kg), or SIN-1 (peroxynitrite generator, 1.5 mg/kg) for 15min at the onset of reperfusion. Some of the D rats were injected with APN adenovirus (1X109 pfu) 7 days before inducing IRI. Cultured rat cardiac H9C2 cells exposed to normal glucose (NG, 5mM) or high glucose (HG, 30 mM) were subjected to 45min hypoxia and 90min reoxygenation (H/R) without or with HO-1, STAT3, or APN gene knock-down achieved by siRNA infection. RESULTS: 33& VLJQL¿FDQWO UHGXFH SRVW LVFKHPLF PRFDUGLDO infarct size and plasma creatine kinase-MB release, accompanied with improved cardiac functions manifested as increased end systolic pressure and dP/dtmax, decreased end diastolic pressure and dP/dtmin in C rats (all P<0.05 PPC vs. C), concomitant with decreased peroxynitrite production and increased cardiac HO-1 and STAT3 phosphorylation (p-STAT3) at site Tyr705. All these changes were enhanced by the FeTPPS but abolished by SIN-1 (all P<0.05 33& YV & 6LPLODUO 33& VLJQL¿FDQWO UHGXFHG SRVW KSR[LF lactate dehydrogenase release and apoptotic cells in cultured H9C2 cells exposed to NG, where these cellular protection of PPC were cancelled by either HO-1 or STAT3 gene knock-down. However, cardioprotective effects of PPC were abolished in D rats and HG treated H9C2 cells, which was associated with decreased APN. APN supplementation restored PPC cardioprotection in D rats or HG treated cells, accompanied with increased p-STAT3 but not HO-1 expression, while STAT3 or APN gene knockdown but not HO-1 gene knockdown abolished APN-mediated restoration of PPC cardioprotection. CONCLUSIONS: Under normal condition, PPC confers cardioprotection by HO-1-dependent STAT3 activation subsequent to reducing peroxynitrite, while under hyperglycemic condition, PPC confers cardioprotection via APN-dependent STAT3 activation. REFERENCES: 1. Clin Sci (Lond) 121:57-69 2. Free Radic Biol Med, 63C, 291-303