A Stress Inducible Protein Sestrin2 in Heart Failure

心力衰竭是一个日益普遍的问题，尤其是在老年退伍军人中 人口从临床角度来看，肥胖、糖尿病、 COPD（慢性阻塞性肺疾病），这些患者的衰老和高血压导致了 炎症假说，其中心力衰竭也与冠状动脉微血管功能障碍有关。 然而，不适应的底物代谢和受损的冠状动脉血流的因果关系的重要性， 心力衰竭发展中的调控机制尚不清楚。本提案中所述的工作 结合基础和转化研究水平的实验，以满足我们的关键需求 为退伍军人提供新颖有效的心力衰竭疗法。我们研究的长期目标是 了解Sestrin 2（Sesn 2）作用的分子机制， 蛋白，介导从代偿性左心室肥厚到失代偿性 肥厚和适应不良的心室重构。我们已经证明了Sesn 2是 是生理性和病理性心脏肥大的介质，现在正在寻求定义 潜在的分子机制。Sesn 2敲除（Sesn 2 KO）小鼠在200 ℃时显示正常的心脏功能。 与野生型（WT）同窝出生仔相比， 压力过载此外，我们实验室最近公布的数据表明，Sesn 2作为一个年龄- 一种调节AMPK的相关蛋白，AMPK是一种心脏能量传感器，可在心肌缺血时维持代谢稳态。 应力条件衰老相关的心力衰竭可能是由于受损的Sesn 2-AMPK信号级联反应 与高血压的副作用协同发生。因此，我们的中心假设是Sesn 2 作为一种支架蛋白，在高血压诱导的老年心力衰竭中发挥关键作用。目标1： 确定控制心脏Sesn 2表达的上游信号通路， Sesn 2介导的AMPK信号传导可抑制高血压诱导的心力衰竭的发展 衰老目的2：探讨Sesn 2-mTORC 1复合物在高血压心脏反应中的作用 和衰老。我们的长期目标是通过开发一种 更好地了解导致心力衰竭的机制，并确定新的靶向治疗方法 可以预防或逆转高血压性心力衰竭。

Heart failure is an increasingly prevalent problem and particularly so amongst an aging Veterans population. From a clinical standpoint, the prevalence of comorbid conditions such as obesity, diabetes, COPD (chronic obstructive pulmonary disease), aging and hypertension in these patients has led to the inflammatory hypothesis where heart failure is also associated with coronary microvascular dysfunction. Nevertheless, the causal importance of maladaptive substrate metabolism and impaired coronary flow regulation in the development of the heart failure remain unclear. The work described in this proposal combines experiments at the basic and translational research level to address the critical need of our veterans for novel and effective heart failure therapies. The long-term goal of our research is to understand the molecular mechanisms that underlie the role of Sestrin2 (Sesn2), a stress inducible protein, in mediating progression from compensated left ventricular hypertrophy to decompensated hypertrophy and maladaptive ventricular remodeling in heart failure. We have demonstrated that Sesn2 is a mediator of physiologic and pathologic cardiac hypertrophy and are now seeking to define the underlying molecular mechanisms. Sesn2 knockout (Sesn2 KO) mice display normal cardiac function at rest compared to wild type (WT) littermates but are vulnerable with pathologic hypertrophy in response to pressure overload. Furthermore, recently published data from our lab show that Sesn2 serves as an age- related protein that modulates AMPK, a cardiac energy sensor, to maintain metabolic homeostasis under stress conditions. Aging related heart failure could be due to impaired Sesn2-AMPK signaling cascade occurring in synergy with the adverse effects of hypertension. Thus, our central hypothesis is that Sesn2 serves as a scaffold protein that plays a key role in hypertension induced heart failure in aging. Aim 1: To determine the upstream signaling pathways that control cardiac Sesn2 expression, and the mechanisms by which Sesn2-mediated AMPK signaling inhibits development of hypertension-induced heart failure in aging. Aim 2: To determine the role of Sesn2-mTORC1 complex in the cardiac response to hypertension and aging. Our long-term objective is to improve the care of Veterans with heart failure by developing a better understanding of the mechanisms leading to heart failure and identifying novel targeted treatments that can prevent or reverse hypertensive heart failure.