Activation of sirtuins to prevent adverse cardiac remodeling after CABG

描述（由申请人提供）：充血性心力衰竭（HF）是世界范围内死亡和并发症的主要原因之一。即使在冠状动脉旁路移植术（CABG）完全血运重建后，心肌梗死患者也经常在远端心肌发生不良心室重构，从而产生导致心衰的并发症。人类和动物研究都表明，心脏的生化和机械应力导致心肌细胞肥大，心脏成纤维细胞（CF）分化为肌成纤维细胞（myoFB），并沉积细胞外基质（ECM），导致不利的心室重构。CF转化为myoFB的潜在机制尚不完全清楚。需要新的方法来定义这一病理过程背后的机制，并确定新的治疗策略来保护心肌梗死后心脏不下降到衰竭。我的实验室对sirtuins特别感兴趣，它能够激活细胞内抗氧化防御机制并延长物种的寿命。我的实验室最近的工作已经确定了sirtuin的一种异构体SIRT3作为心脏肥厚的内源性负调节因子。sirt3缺陷小鼠发生与间质纤维化相关的心脏肥大，而转基因小鼠心脏特异性过表达

DESCRIPTION (provided by applicant): Congestive heart failure (HF) is one of the leading causes of death and complications worldwide. Even after complete revascularization by coronary artery bypass grafting (CABG) patients with MI (myocardial infarction) often develop adverse ventricular remodeling in the remote myocardium which generates complications leading to HF. Both human and animal studies have demonstrated that biochemical and mechanical stress on the heart leads to cardiac myocyte hypertrophy and cardiac fibroblasts (CF) differentiation to myofibroblasts (myoFB) which deposit extracellular matrix (ECM), leading to adverse ventricular remodeling. The underlying mechanism of CF transformation to myoFB is not yet fully understood. New approaches are needed to define the mechanism behind this pathological process, and to identify new therapeutic strategies to protect the heart from descending to failure post MI. My laboratory has specific interest in sirtuins, which are capable of activating intracellular anti-oxidant defense mechanisms and extending life-span of species. Recent work from my laboratory has identified one sirtuin isoform, SIRT3 as an endogenous negative regulator of cardiac hypertrophy. SIRT3-deficent mice develop cardiac hypertrophy associated with interstitial fibrosis, and transgenic mice with cardiac-specific over expression of SIRT3 are protected from developing hypertrophy. We also found that SIRT3 (-/-) fibroblasts are highly permissive to myoFB transformation, but not the fibroblasts over expressed with SIRT3. Additional studies done with human hearts showed that SIRT3 levels are dramatically reduced in patients with ischemic cardiomyopathy, and over expression of SIRT3 blocks pro-fibrotic effects of Ang-II on human CF in vitro. Based on these findings we hypothesized that loss of SIRT3 may be a cause of CF transformation to myoFB, and thus by maintaining cellular SIRT3 levels CF differentiation to myoFB can be blocked, and heart could be protected from developing fibrosis and HF. To test this hypothesis we propose three specific aims: (1) Study the role of SIRT3 in regulating adult human CF transformation to myoFB and the maladaptive cardiac remodeling. (2) Determine underlying mechanisms through which SIRT3 blocks human CF proliferation and transformation. (3) Test whether SIRT3 activation can be used as a novel therapeutic strategy to block maladaptive LV remodeling following MI in an animal model. A successful outcome of these three aims will have major impact on our understanding of the disease process of ventricular remodeling, and that this may guide us to identify new therapeutic targets critical for translational medicine of HF.