Improving post-surgery recovery of failing hearts by targeting cardiomyocyte senescence

通过靶向心肌细胞衰老来改善衰竭心脏的术后恢复

• 批准号: 9753360
• 负责人: MAHESH P GUPTA
• 金额: $ 43.01万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753360
• 关键词: Aging; Angiotensinogen; Biological Process; Blood Vessels; CDKN2A gene; Caloric Restriction; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiac development; Cardiovascular system; Cause of Death; Cell Aging; Cell Nucleus; Cells; Chondrocytes; Clinical; Coronary Arteriosclerosis; Coronary Artery Bypass; DNA Damage; Development; Diet; Disease; Disease Management; Down-Regulation; Elderly; Enzymes; Evolution; Extracellular Matrix; Fibroblasts; Fibrosis; Growth; Growth Factor; Health; Heart; Heart Block; Heart Hypertrophy; Heart Transplantation; Heart failure; Human; Inferior; Inflammation; Inflammatory; Injury; Insulin Resistance; Kidney Failure; Laboratories; Longevity; Malignant Neoplasms; Mechanics; Mediating; Medical; Medicine; Metabolism; Mitochondria; Mus; Musculoskeletal Diseases; Myocardial; Myocardial Infarction; Myofibroblast; Operative Surgical Procedures; Organ; Outcome; Oxidative Stress; Parents; Pathogenesis; Pathologic; Pathologic Processes; Patients; Pharmacology; Phenotype; Process; Protein Isoforms; Pulmonary Fibrosis; Recovery; Regimen; Reporting; Risk Factors; Role; SIRT1 gene; Signal Transduction; Sirtuins; Surgical complication; TP53 gene; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; Treatment Efficacy; Ventricular; Western World; analog; base; body system; cardiogenesis; cell growth; chemokine; coronary fibrosis; cytokine; density; heart damage; heart function; implantation; improved; loss of function; mammalian genome; mouse model; novel strategies; novel therapeutics; overexpression; prevent; reconstruction; response; senescence; surgery outcome; telomere; tumor; ventricular assist device

Summary: In the last decade, with advancements in medical therapies and surgical interventions survivability of patients with heart failure (HF) has improved, but a significant number of patients still progress to end-stage HF, where treatment options largely limited to cardiac transplantation. As patients demand for transplant continue to exceed the organ supply, new approaches needed to understand the mechanism behind the progression of HF and to develop new therapies to delay or prevent its development. With surgical interventions like coronary artery bypass grafting and ventricular assist device implantation, patients with advanced age (65+ years) often show inferior recovery despite complete revascularization and unloading of the heart. The underlying cause of this pathologic process not yet completely understood, but it has been realized that cardiac aging contributes significantly to this pathologic outcome. Recent studies indicate that aging hearts accumulate senescent cardiomyocytes, which secrete pro-inflammatory cytokines, chemokines and growth factors, known as SASP (senescence-associated secretory phenotype). While SASP causes destruction of the parent cell, it also activates neighboring fibroblasts to transform into myofibroblasts, leading to progressive cardiac fibrosis and HF. Many previous reports demonstrated that elimination of senescent cells mitigates aging-associated diseases, including cancer, renal failure, pulmonary fibrosis and musculoskeletal diseases. However, a role of cardiomyocyte senescence in progressive ventricular fibrosis and post-surgery recovery of failing hearts never studied. My laboratory is working on a sirtuin analogue Sirt6, which extends lifespan of mice. We found reduced Sirt6 levels in aging hearts and during development of HF. In cardiomyocytes Sirt6 depletion induced p53 & p16INK4a expression and mitochondrial destruction, markers of senescence. We also found that cardiomyocyte SASP activates fibroblasts to transform into myofibroblasts. These findings prompted us to propose the hypothesis that Sirt6 has potential to block cardiomyocyte senescence and SASP-mediated activation of fibroblasts to synthesize excessive extracellular matrix. Therefore, by augmenting Sirt6, we can prevent development of progressive cardiac fibrosis and improve post-surgery recovery of failing hearts undergoing surgical interventions. To test this hypothesis, we developed two transgenic mouse lines, in which Sirt6 overexpressed either specifically in cardiomyocytes or globally in all tissues. We will test this hypothesis in three aims. Aim 1: Study whether Sirt6 activation blocks cardiomyocyte senescence and fibroblast activation, and development of progressive cardiac fibrosis in the mouse models of HF. Aim 2: Determine the underlying mechanism of Sirt6 downregulation and the mechanism by which Sirt6 blocks cardiomyocyte senescence. Aim 3: test the translational potential of a Sirt6 activator to protect the aging heart from developing cardiomyocyte-senescence and post-injury progressive cardiac fibrosis and HF. We believe by completing these aims, we will determine a basic mechanism of why aging hearts respond poorly to post-surgery recovery, and a new therapy to improve it.

摘要：在过去的十年里，随着医学治疗和外科干预的进步， 心力衰竭(HF)患者的病情有所改善，但仍有相当数量的患者进展到终末期HF， 治疗选择很大程度上局限于心脏移植。随着患者对移植的需求继续增加 超过器官供应，需要新的方法来理解心力衰竭进展背后的机制 并开发新的治疗方法来延缓或阻止其发展。像冠状动脉这样的外科手术 高龄(65岁以上)患者常表现为搭桥术和脑室辅助装置植入 尽管心脏完全血运重建和卸载，但恢复较差。造成这种情况的根本原因是 病理过程尚不完全清楚，但已认识到心脏老化在其中的作用。 对这一病理结果有重大影响。最近的研究表明，老化的心脏会累积衰老。 心肌细胞，分泌促炎细胞因子、趋化因子和生长因子，称为SASP (衰老相关的分泌表型)。虽然SASP会破坏父细胞，但它也会激活 邻近的成纤维细胞转化为肌成纤维细胞，导致进行性心脏纤维化和心衰。许多 以前的报告表明，消除衰老细胞可以缓解与衰老相关的疾病，包括 癌症、肾功能衰竭、肺纤维化和肌肉骨骼疾病。然而，心肌细胞的一个作用是 进行性心室纤维化中的衰老和衰竭心脏手术后的恢复从未被研究过。我的 实验室正在研究一种sirtuin类似物SIRT6，它可以延长小鼠的寿命。我们发现SIRT6水平降低了 在老化的心脏和心力衰竭的发展过程中。心肌细胞中SIRT6缺失诱导的p53和p16INK4a 表达和线粒体破坏是衰老的标志。我们还发现，心肌细胞SASP 激活成纤维细胞转化为肌成纤维细胞。这些发现促使我们提出了这样的假设 SIRT6具有阻断心肌细胞衰老和SASP介导的成纤维细胞合成 细胞外基质过多。因此，通过增强SIRT6，我们可以防止进行性疾病的发展 心脏纤维化和改善接受手术干预的衰竭心脏手术后的恢复。为了测试这一点 假设，我们发展了两个转基因小鼠系，其中SIRT6在 心肌细胞或所有组织中的整体。我们将在三个目标上检验这一假设。目标1：研究SIRT6是否 激活阻断心肌细胞衰老和成纤维细胞的激活，以及进展性心脏的发展 心衰小鼠模型中的纤维化。目标2：确定SIRT6下调的潜在机制和 SIRT6抑制心肌细胞衰老的机制。目标3：测试SIRT6的翻译潜力 保护老化心脏免受心肌细胞衰老和损伤后进展的激活剂 心脏纤维化和心力衰竭。我们相信，通过完成这些目标，我们将确定为什么衰老的基本机制 心脏对术后恢复的反应很差，有一种新的治疗方法来改善它。