Activation of sirtuins to prevent adverse cardiac remodeling after CABG

激活sirtuins以预防CABG后不良心脏重塑

• 批准号: 8440040
• 负责人: MAHESH P GUPTA
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440040
• 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; Functional disorder; Genetic Transcription; Goals; 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; Myocardial Infarction; 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; heart function; in vivo; interest; interstitial; man; mange; new therapeutic target; novel strategies; novel therapeutics; prevent; public health relevance; research study; response; translational medicine; treatment strategy

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(申请人提供)：充血性心力衰竭(HF)是世界范围内导致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(MI)患者往往会在远端心肌发生不利的室壁重构，从而产生并发症，导致心力衰竭。人类和动物的研究都表明，生物化学和机械应激对心脏造成心肌细胞肥大，心脏成纤维细胞(CF)分化为肌成纤维细胞(MyoFB)，后者沉积细胞外基质(ECM)，导致不利的心室重构。Cf向myoFB转化的潜在机制尚不完全清楚。需要新的方法来确定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免于下降到衰竭。我的实验室对sirtuins特别感兴趣，它能够激活细胞内的抗氧化防御机制，延长物种的寿命。我的实验室最近的工作发现了一种sirtuin亚型，SIRT3，它是心肌肥厚的内源性负调控因子。SIRT3缺陷小鼠出现与间质纤维化相关的心肌肥大，心脏特异性过表达的转基因小鼠 SIRT3受到保护，不会发展为肥大。我们还发现，SIRT3(-/-)成纤维细胞对myoFB转化高度允许，但不能过度表达SIRT3的成纤维细胞。对人心脏的进一步研究表明，在缺血性心肌病患者中，SIRT3水平显著降低，SIRT3的过度表达可以阻断Ang-II在体外对人CFs的促纤维化作用。基于这些发现，我们推测SIRT3的缺失可能是CF向myoFB转化的原因之一，因此，通过维持细胞SIRT3水平，可以阻止CF向myoFB的分化，从而保护心脏免受纤维化和心力衰竭的影响。为了验证这一假说，我们提出了三个具体的目标：(1)研究SIRT3在调节成人CF向myoFB转化和不良适应性心脏重构中的作用。(2)确定SIRT3阻断人CFs增殖和转化的潜在机制。(3)检测SIRT3的激活是否可以作为一种新的治疗策略来阻断心肌梗死后适应性不良的左室重构。这三个目标的成功实现将对我们理解心室重构的疾病过程产生重大影响，并可能指导我们寻找对翻译医学至关重要的新的治疗靶点。