Activation of sirtuins to prevent adverse cardiac remodeling after CABG

激活sirtuins以预防CABG后不良心脏重塑

基本信息

批准号：
8789384
负责人：
MAHESH P GUPTA
金额：
$ 38.91万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789384
关键词：
Abdomen Adult Agonist Animal Model Animals Antioxidants Apoptosis Biochemical Biological Biological Process Cardiac Cardiac Myocytes Cardiomyopathies Cause of Death Cell Death Cell Nucleus Congestive Heart Failure Connective Tissue Contractile Proteins Coronary Arteriosclerosis Coronary Artery Bypass Cytoskeleton Defense Mechanisms Deposition Development Disease Echocardiography Extracellular Matrix Extracellular Matrix Proteins Failure Fibroblasts Fibrosis Genetic Transcription Geometry Goals Health Heart Heart Block Heart Diseases Heart Hypertrophy Heart failure Human Hypertrophy Implant In Vitro Infarction Inferior Injury Ischemia Laboratories Left Ventricular Remodeling Ligation Link Longevity Magnetic Resonance Imaging Mammalian Cell Mechanical Stress Mediating Modeling Molecular Biology Mus Myocardial Infarction Myocardial dysfunction Myocardium Myofibroblast Natural regeneration Operative Surgical Procedures Organ Outcome Oxidative Stress Pathologic Processes Patients Play Procedures Process Production Protein Biosynthesis Protein Isoforms Proteins Pump Rattus Regulation Role Signal Transduction Sirtuins Smooth Muscle Actin Staining Method Stimulus Testing Time Tissues Transgenic Mice Ventricular Remodeling Wild Type Mouse Work base cell growth coronary fibrosis heart function in vivo interest interstitial man mange new therapeutic target novel strategies novel therapeutics prevent research study response translational medicine treatment strategy

项目摘要

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.

描述（由申请人提供）：充血性心力衰竭（HF）是全世界死亡和并发症的主要原因之一。即使在通过冠状动脉旁路移植术 (CABG) 进行完全血运重建后，MI（心肌梗死）患者也经常在远端心肌中发生不良心室重构，从而产生导致心力衰竭的并发症。人类和动物研究都表明，心脏的生化和机械应力会导致心肌细胞肥大和心肌成纤维细胞 (CF) 分化为肌成纤维细胞 (myoFB)，从而沉积细胞外基质 (ECM)，从而导致不利的心室重塑。 CF 转化为 myoFB 的基本机制尚未完全清楚。需要新的方法来定义这种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免于下降至衰竭。我的实验室对去乙酰化酶特别感兴趣，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发现了一种沉默调节蛋白异构体 SIRT3，它是心脏肥大的内源性负调节因子。 SIRT3 缺陷小鼠出现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 SIRT3 SIRT3 受到保护，不会发生肥大。我们还发现 SIRT3 (-/-) 成纤维细胞高度允许 myoFB 转化，但 SIRT3 过度表达的成纤维细胞则不然。对人类心脏进行的其他研究表明，缺血性心肌病患者的 SIRT3 水平显着降低，并且 SIRT3 的过度表达可阻断 Ang-II 在体外对人类 CF 的促纤维化作用。基于这些发现，我们假设 SIRT3 的缺失可能是 CF 转化为 myoFB 的原因，因此通过维持细胞 SIRT3 水平，可以阻止 CF 分化为 myoFB，并且可以保护心脏免于发生纤维化和心力衰竭。为了检验这一假设，我们提出了三个具体目标：（1）研究 SIRT3 在调节成人 CF 向 myoFB 转化和适应不良心脏重塑中的作用。 (2) 确定 SIRT3 阻断人 CF 增殖和转化的潜在机制。 (3) 测试 SIRT3 激活是否可以作为一种新的治疗策略来阻止动物模型中 MI 后适应不良的 LV 重塑。这三个目标的成功实现将对我们对心室重构疾病过程的理解产生重大影响，这可能会指导我们确定对心力衰竭转化医学至关重要的新治疗靶点。