Rationale: Coronary artery ligation to induce myocardial infarction (MI) in mice is typically performed by an invasive and time-consuming approach that requires ventilation and chest opening (classic method), often resulting in extensive tissue damage and high mortality. We developed a novel and rapid surgical method to induce MI that does not require ventilation.Objective: The purpose of this study was to develop and comprehensively describe this method and directly compare it to the classic method. Key Words: myocardial ischemia Ⅲ myocardial ischemia/reperfusion injury Ⅲ cardiac injury Ⅲ cardiac dysfunction Ⅲ mouse model C ardiovascular disease represents the leading cause of morbidity and death in developed countries. Coronary heart disease, which is the single largest cause of cardiovascular disease, is the narrowing of arteries over time caused by atherosclerotic plaques or the acute occlusion of the coronary artery by thrombosis, both of which lead to possible myocardial infarction (MI) and the eventual development of heart failure. 1,2 Protection from coronary heart disease-induced damage of the myocardium during myocardial ischemia/ reperfusion (I/R) injury has been a target of investigation for the development of innovative cardioprotective therapies. [3][4][5][6][7] The increase in the availability of various types of genetically manipulated mice has brought about the need for more efficient ways to induce myocardial damage for both molecular mechanistic studies and potentially therapeutic interventions. Two of the most common models used by researchers are permanent left main descending coronary artery (LCA) occlusion to induce a MI and also temporary coronary artery occlusion to induce I/R injury. 8,9 The I/R model is generally used to examine the short-term consequences of ischemic injury, whereas the MI model is usually used to investigate myocardial changes such as remodeling that occur over an extended period of time. Although a variety of surgical manipulations have been used during the past decade to induce the ischemic event, ligation of the LCA is still the most commonly practiced method. 3,9 -11 However, most investigators still use a method requiring ventilation and wide opening the chest (referred to as the classic method), which can cause extensive tissue damage, high surgical-related death and can also be quite time consuming for most surgeons. [12][13][14][15] Over the last few years, we have developed a new MI approach in mice that does not require ventilation. 11,16 -18 Complete characterization and description of this model has Original Methods and Results:

Background-Several clinical studies have demonstrated that levels of adiponectin are significantly reduced in patients with type 2 diabetes and that adiponectin levels are inversely related to the risk of myocardial ischemia. The present study was designed to determine the mechanism by which adiponectin exerts its protective effects against myocardial ischemia/reperfusion. Methods and Results-AdiponectinϪ/Ϫ or wild-type mice were subjected to 30 minutes of myocardial ischemia followed by 3 hours or 24 hours (infarct size and cardiac function) of reperfusion. Myocardial infarct size and apoptosis, production of peroxynitrite, nitric oxide (NO) and superoxide, and inducible NO synthase (iNOS) and gp91 phox protein expression were compared. Myocardial apoptosis and infarct size were markedly enhanced in adiponectin Ϫ/Ϫ mice (PϽ0.01). Formation of NO, superoxide, and their cytotoxic reaction product, peroxynitrite, were all significantly higher in cardiac tissue obtained from adiponectin Ϫ/Ϫ than from wild-type mice (PϽ0.01). Moreover, myocardial ischemia/ reperfusion-induced iNOS and gp91 phox protein expression was further enhanced, but endothelial NOS phosphorylation was reduced in cardiac tissue from adiponectin Ϫ/Ϫ mice. Administration of the globular domain of adiponectin 10 minutes before reperfusion reduced myocardial ischemia/reperfusion-induced iNOS/gp91 phox protein expression, decreased NO/superoxide production, blocked peroxynitrite formation, and reversed proapoptotic and infarctenlargement effects observed in adiponectin Ϫ/Ϫ mice. Conclusion-The present study demonstrates that adiponectin is a natural molecule that protects hearts from ischemia/ reperfusion injury by inhibition of iNOS and nicotinamide adenine dinucleotide phosphate-oxidase protein expression and resultant oxidative/nitrative stress.

Background-Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in apoptotic cell death.The role of p38 MAPK in myocardial injury caused by ischemia/reperfusion, an extreme stress to the heart, is unknown.

SUMMARY Adiponectin is an abundant plasma protein secreted from adipocytes that elicits protective effects in the vasculature and myocardium. In obesity and insulin-resistant states, adiponectin levels are reduced and loss of its protective effects might contribute to the excess cardiovascular risk observed in these conditions. Adiponectin ameliorates the progression of macrovascular disease in rodent models, consistent with its correlation with improved vascular outcomes in epidemiological studies. The mechanisms of adiponectin signaling are multiple and vary among its cellular sites of action. In endothelial cells, adiponectin enhances production of nitric oxide, suppresses production of reactive oxygen species, and protects cells from inflammation that results from exposure to high glucose levels or tumor necrosis factor, through activation of AMP-activated protein kinase and cyclic AMP-dependent protein kinase (also known as protein kinase A) signaling cascades. In the myocardium, adiponectin-mediated protection from ischemia-reperfusion injury is linked to cyclo-oxygenase-2-mediated suppression of tumor necrosis factor signaling, inhibition of apoptosis by AMP-activated protein kinase, and inhibition of excess peroxynitrite-induced oxidative and nitrative stress. In this Review, we provide an update of studies of the signaling effects of adiponectin in endothelial cells and cardiomyocytes.