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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：
10199774
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199774
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 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 dietary 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，随着医学治疗和手术干预的进步，生存能力