Reduced Cardioprotective Action of Adiponectin in High-Fat Diet–Induced Type II Diabetic Mice and Its Underlying Mechanisms

Abstract

Diabetes exacerbates ischemic heart disease morbidity and mortality via incompletely understood mechanisms. Although adiponectin (APN) reduces myocardial ischemia/reperfusion (MI/R) injury in nondiabetic animals, whether APN's cardioprotective actions are altered in diabetes, a pathologic condition with endogenously reduced APN, has never been investigated. High-fat diet (HD)-induced diabetic mice and normal diet (ND) controls were subjected to MI via coronary artery ligation, and given vehicle or APN globular domain (gAPN, 2 mg/g) 10 min before reperfusion. Compared to ND mice (where gAPN exerted pronounced cardioprotection), HD mice manifested greater MI/R injury, and a tripled gAPN dose was requisite to achieve cardioprotective extent seen in ND mice (i.e., infarct size, apoptosis, and cardiac function). APN reduces MI/R injury via AMPactivated protein kinase (AMPK)-dependent metabolic regulation and AMPK-independent antioxidative/ antinitrative pathways. Compared to ND, HD mice manifested significantly blunted gAPN-induced AMPK activation, basally and after MI/R ( p < 0.05). Although both low-and high-dose gAPN equally attenuated MI/ R-induced oxidative stress (i.e., NADPH oxidase expression and superoxide production) and nitrative stress (i.e., inducible nitric oxide synthase expression, nitric oxide production, and peroxynitrite formation) in ND mice, only high-dose gAPN efficaciously did so in HD mice. We demonstrate for the first time that HD-induced diabetes diminished both AMPK-dependent and AMPK-independent APN cardioprotection, suggesting an unreported diabetic heart APN resistance. Antioxid. Redox Signal. 15, 1779-1788.

Hyperglycemia Abrogates Ischemic Postconditioning Cardioprotection by Impairing AdipoR1/Caveolin-3/STAT3 Signaling in Diabetic Rats

“…Furthermore, the finding that antioxidant treatment enhanced STAT3 activation in the heart of diabetic rats through APN signaling (9) suggests that malfunction of APN might be a key mechanism that rendered the diabetic heart less or not responsive to IPo cardioprotection. In addition, cardioprotective effects of APN were diminished in high-fat diet-induced diabetes (10,11), in which Cav3 is downregulated (12). This, together with our recent finding that Cav3 is disrupted (13) and STAT3 inactivated (9), which deranged eNOS signaling in diabetic myocardium with concomitantly reduced APN (9), indicates that APN signaling (e.g., AdipoR1/Cav3) is impaired in diabetes.…”

“…In addition to type 1 diabetes, IPo cardioprotective effects were also reduced in type 2 diabetes (44), and we have shown that APN cardioprotective effects also reduced in type 2 diabetes associated with reduced APN content (10,11). However, whether IPo can increase the interaction of AdipoR1 and Cav3 in type 2 diabetes is not known.…”

Role of Adipokines in Cardiovascular Disease

“…97 However, in dissimilar fashion to APN-deficient mice (which lack phenotypic changes under physiologic conditions), CTRP9-deficient mice are obese, insulin resistant, and exhibit hepatic steatosis with reduced skeletal muscle AMPK activation and mitochondrial content. 84 Such results are genetic evidence for a physiologic role of CTRP9, suggesting that CTRP9 may play a significant role in cardiovascular homeostasis. Additionally, CTRP9 primarily circulates in the plasma as the gCTRP9 isoform.…”

“…This is different tective effect of APN. 84 As mentioned before, the efficacy of recombinant exogenous APN in ameliorating myocardial I/R disease has been demonstrated in multiple animal studies. The practical clinical application of exogenous recombinant APN is limited for multiple reasons such as APN's complex quaternary structure, rapid turnover, and the high cost of pro- Figure 4.…”

“…39 It is composed of the structural protein caveolin (Cav), AdipoR1, APPL1 (the most important molecule in APN's AMPK-dependent signaling), and adenylate cyclase and neutral ceramidase (2 important molecules in APN's AMPK-independent signaling). 84 The interaction between AdipoR1 and caveolin is required for proper APN-mediated signaling. Treatment with high glucose/high lipid disrupts the AdipoR1/Cav signalosome, leading to APN resistance.…”