The Role of Adiponectin in Ischemia-Reperfusion Injury in the Type 2 Diabetic Heart

Abstract

Cardiovascular disease (CVD) is the leading cause of death in the United States, and the risk and severity of CVD are increased with type 2 diabetes. However, the exact mechanisms that result in the enhanced association between CVD and type 2 diabetes have not been clearly elucidated. Inflammation and oxidative stress are strongly implicated in both diseases. In type 2 diabetes, there is a dysregulation of inflammatory mediators where an anti-inflammatory molecule adiponectin and a pro-inflammatory cytokine TNF-alpha, are reduced and increased, respectively. Even lower plasma adiponectin concentrations are associated in type 2 diabetic patients with cardiovascular disease. Thus, adiponectin may be a significant link between the two diseases. The studies in this dissertation examined the in vivo cardioprotective actions of adiponectin and apocynin, a NADPH oxidase inhibitor, in the Zucker diabetic fatty (ZDF) type 2 diabetic model. A model of coronary artery occlusion was utilized to induce myocardial ischemia-reperfusion (I/R) injury. The mechanisms of protective actions were assessed by measures of inflammation, oxidative stress and DNA damage. Further, in vitro actions of adiponectin in human whole blood were investigated. We found that in vivo treatments of adiponectin and apocynin significantly reduced myocardial infarction in the type 2 diabetic heart by 40% and 68%, respectively. The cardioprotective action of adiponectin was associated with 2 to 4 fold significant attenuations in several inflammatory characteristics, such as neutrophil adhesion molecule CD11b expression, myocardial adhesion molecule ICAM-1 expression, myocardial neutrophil accumulation and plasma TNF-alpha concentration. The cardioprotective action of apocynin was associated with a significant reduction in myocardial oxidative stress by 25%. In vitro adiponectin actions demonstrated the ability of adiponectin to reduce neutrophil ROS production in human whole blood. These studies were the first to report the cardioprotective action of adiponectin in the type 2 diabetic heart. In addition, adiponectin was found to modulate neutrophil-mediated myocardial I/R injury. Collectively, these findings indicate the significant role of adiponectin in inflammation and oxidative stress in type 2 diabetes. Further, it can be concluded that inflammation and oxidative stress significantly contribute to the enhanced severity of injury observed in the type 2 diabetic heart.