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

基本信息

批准号：
9978930
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
项目类别：
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/9978930
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 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 myocardial injury novel strategies novel therapeutics overexpression prevent reconstruction response senescence surgery outcome telomere tumor ventricular assist device

项目摘要

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：在过去的十年中，随着药物治疗和手术干预的进步，心力衰竭 (HF) 患者已有所改善，但仍有相当一部分患者进展为终末期 HF，其中治疗选择主要限于心脏移植。随着患者对移植的需求不断增加超过器官供应，需要新方法来了解心力衰竭进展背后的机制并开发新疗法来延迟或阻止其发展。通过冠状动脉等手术干预旁路移植术和心室辅助装置植入，高龄（65岁以上）患者经常表现出尽管完全血运重建和心脏卸载，恢复仍较差。造成这一现象的根本原因病理过程尚未完全了解，但已认识到心脏衰老会导致对这种病理结果有显着影响。最近的研究表明，衰老的心脏会积累衰老细胞心肌细胞，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 会破坏母细胞，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力衰竭。许多之前的报告表明，消除衰老细胞可以减轻与衰老相关的疾病，包括癌症、肾衰竭、肺纤维化和肌肉骨骼疾病。然而，心肌细胞的作用进行性心室纤维化中的衰老和衰竭心脏的术后恢复从未被研究过。我的实验室正在研究一种沉默调节蛋白类似物 Sirt6，它可以延长小鼠的寿命。我们发现 Sirt6 水平降低在衰老的心脏和心力衰竭的发展过程中。在心肌细胞中 Sirt6 耗竭诱导 p53 和 p16INK4a 表达和线粒体破坏，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以下假设： Sirt6 具有阻止心肌细胞衰老和 SASP 介导的成纤维细胞合成激活的潜力细胞外基质过多。因此，通过增强 Sirt6，我们可以防止进行性进展的发展心脏纤维化并改善接受手术干预的衰竭心脏的术后恢复。为了测试这个假设，我们开发了两个转基因小鼠品系，其中 Sirt6 过表达心肌细胞或全球所有组织中。我们将从三个目标来检验这个假设。目标 1：研究 Sirt6 是否激活可阻止心肌细胞衰老和成纤维细胞激活，以及进行性心脏疾病的发展心衰小鼠模型中的纤维化。目标 2：确定 Sirt6 下调的根本机制以及 Sirt6 阻断心肌细胞衰老的机制。目标 3：测试 Sirt6 的转化潜力保护衰老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，我们将确定衰老的基本机制心脏对手术后恢复的反应很差，需要一种新的疗法来改善它。