Exploring roles of sirtuins in protecting diabetic hearts

总结：经济改善和繁荣的主要不利因素之一是糖尿病的上升。 久坐不动的生活方式和高热量饮食与糖尿病的发病率上升有关。糖尿病患者在 发生心肌病和心力衰竭（HF）的风险较高。这些患者也经历了最严重的临床 高血压、心肌梗死和心脏手术后的结果。在细胞水平上， 炎症、胰岛素抵抗、心脏肥大和纤维化被认为是糖尿病标志 心肌病然而，这种疾病过程的潜在机制尚未完全阐明， 糖尿病性心肌病的治疗目前还没有靶向治疗。新的方法 需要了解这种疾病背后的机制，并确定新的治疗策略， 防止糖尿病心肌病后心脏衰竭。我的实验室对 在sirtuins（SIRTs）中，sirtuins（SIRTs）正在成为无数生物功能的关键调节因子，从细胞到细胞， 增长、分化到长寿。我们实验室最近的工作已经确定SIRT 6是一种内源性的 心脏肥大的负调节因子。在糖尿病患者的心脏中，我们发现SIRT 6水平显著升高， 减少;这与纤维化，炎性小体形成的活化剂表达增加有关 和胰岛素抵抗。我们还发现，SIRT 6缺陷导致所需基因的表达减少， 维持线粒体的结构和功能。这些发现使我们假设SIRT 6的减少 水平有助于糖尿病性心肌病和随后的HF的发展。因此，糖尿病心脏 可以通过增加心脏SIRT 6水平来防止下降到HF。我们将测试这个假设， 以下三个目的：（目的1）研究SIRT 6的缺失是否有助于与SIRT 6相关的病理变化。 随着糖尿病心肌病的发展，以及SIRT 6过表达转基因小鼠是否 防止糖尿病后发生HF。(Aim 2）研究SIRT 6缺陷的潜在机制 以及SIRT 6维持线粒体健康和保护线粒体的机制。 心脏发展疾病。(Aim 3）研究SIRT 6的药理学靶向是否可以保护 糖尿病性心肌病和心力衰竭。从完成这些目标中获得的知识 对于理解sirtuins在糖尿病性心肌病发病机制中的作用是非常重要的， 这可能与开发治疗糖尿病患者HF的新疗法有关。

Summary: One of the major downsides of improved economy and prosperity is the rise of diabetes-mellitus. Sedentary life-style and high calorie diet are implicated in the rise of diabetes. Patients with diabetes are at high risk of developing cardiomyopathy and heart failure (HF). Such patients also experience worst clinical outcome following, hypertension, myocardial infarction and cardiac surgery. At the cellular level, increased inflammation, insulin-resistance, cardiac hypertrophy and fibrosis are considered hallmarks of diabetic cardiomyopathy. However, the underlying mechanism of this disease process is not yet completely understood, and no targeted therapy is available to treat diabetic cardiomyopathy. New approaches are needed to understand the mechanism behind this disease, and to identify new therapeutic strategies to protect the heart from descending to failure post diabetic cardiomyopathy. My laboratory has specific interests in sirtuins (SIRTs), which are emerging as key regulators of myriad of biological functions, spanning from cell growth, differentiation to longevity. Recent work from our laboratory has identified SIRT6, as an endogenous negative regulator of cardiac hypertrophy. In diabetic hearts, we found that SIRT6 levels were drastically reduced; and this was paralleled with increased expression of activators of fibrosis, inflammasome formation and insulin-resistance. We also found that SIRT6 deficiency leads to decreased expression of genes needed to maintain structure and function of mitochondria. These findings led us to hypothesize that decreased SIRT6 levels contribute to the evolution of diabetic cardiomyopathy and subsequent HF. Therefore, a diabetic heart can be protected from descending to HF by augmenting cardiac SIRT6 levels. We will test this hypothesis in the following three aims: (Aim 1) Study whether loss of SIRT6 contributes to pathologic changes associated with the evolution of diabetic cardiomyopathy, and whether SIRT6 overexpressing transgenic mice are protected from developing HF post diabetes. (Aim 2) Study the underlying mechanism of SIRT6 deficiency during diabetes, and the mechanism through which SIRT6 maintains mitochondrial health and protects the heart from developing the disease. (Aim 3) Study whether pharmacological targeting of SIRT6 can protect the heart from developing diabetic cardiomyopathy and HF. The knowledge gained from completing these aims will be extremely important to understand what roles sirtuins play in pathogenesis of diabetic cardiomyopathy, and that could be pertinent to developing new therapies for treatment of HF in diabetic patients.