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: 8620707
• 负责人: MAHESH P GUPTA
• 金额: $ 38.71万
• 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/8620707
• 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; Geometry; 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（由申请人提供）：充血性心力衰竭（HF）是全球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）进行完全血运重建之后，患有MI（心肌梗死）的患者也经常在远端心肌中发生不良心室重构，这产生导致HF的并发症。人类和动物研究都表明，心脏上的生化和机械应力导致心肌细胞肥大和心脏成纤维细胞（CF）分化为肌成纤维细胞（myofibroblasts，myoFB），其存款细胞外基质（ECM），导致不利的心室重构。CF转化为myoFB的潜在机制尚未完全了解。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，以保护心肌梗死后心脏免于下降至衰竭。我的实验室对sirtuins特别感兴趣，sirtuins能够激活细胞内的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一种sirtuin亚型，SIRT 3作为心脏肥大的内源性负调节因子。SIRT 3缺陷小鼠发生与间质纤维化相关的心脏肥大，而心脏特异性过表达SIRT 3的转基因小鼠发生与间质纤维化相关的心脏肥大。 SIRT 3被保护免于发生肥大。我们还发现，SIRT 3（-/-）成纤维细胞对myoFB转化是高度允许的，但不是用SIRT 3过表达的成纤维细胞。对人类心脏进行的其他研究表明，SIRT 3水平在缺血性心肌病患者中显著降低，并且SIRT 3的过表达在体外阻断Ang-II对人类CF的促纤维化作用。基于这些发现，我们假设SIRT 3的缺失可能是CF转化为myoFB的原因，因此通过维持细胞SIRT 3水平，可以阻断CF向myoFB的分化，并且可以保护心脏免于发生纤维化和HF。为了验证这一假设，我们提出了三个具体的目标：（1）研究SIRT 3在调节成人CF转化为myoFB和适应不良的心脏重构中的作用。(2)确定SIRT 3阻断人CF增殖和转化的潜在机制。(3)在动物模型中测试SIRT 3激活是否可用作阻断MI后适应不良的LV重构的新治疗策略。这三个目标的成功结果将对我们理解心室重构的疾病过程产生重大影响，这可能会指导我们确定HF转化医学的新治疗靶点。