Rationale Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to various concerns. Recently, salutary effects of stem cells have been connected to exosome secretion. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective Determine the effect of ESC-derived exosome for the repair of ischemic myocardium and whether c-kit+ CPCs function can be enhanced with ESC exosomes Methods and Results This study demonstrates that mouse ESC derived exosomes (mES Ex) possess ability to augment function in infarcted hearts. mES Ex enhanced neovascularization, cardiomyocyte survival and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex augmented cardiac progenitor cell (CPC) survival, proliferation and cardiac commitment concurrent with increased c-kit+ CPCs in vivo 8 weeks after in vivo transfer along with formation of bonafide new cardiomyocytes in the ischemic heart. miRNA array revealed significant enrichment of miR290–295 cluster and particularly miR-294 in ESC exosomes. The underlying basis for the beneficial effect of mES Ex was tied to delivery of ESC specific miR-294 to CPCs promoting increased survival, cell cycle progression and proliferation. Conclusions mES Ex provide a novel cell free system that utilizes the immense regenerative power of ES cells while avoiding the risks associated with direct ES or ES derived cell transplantation and risk of teratomas. ESC exosomes possess cardiac regeneration ability and modulate both cardiomyocyte and CPC based repair programs in the heart.

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:

SUMMARY Cardiac contractility is mediated by variable flux in intracellular calcium (Ca2+), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu−/− mice display no overt baseline phenotype and are protected against mCa2+-overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu−/− mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca2+-dependent metabolism during acute stress.

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.