Post-Infarction Remodeling in the Diabetic Myocardium

描述（由申请人提供）：糖尿病患者患有几种心血管并发症，包括高脂血症、动脉粥样硬化、心肌梗死（MI）风险增加和整体心脏功能下降。还认识到糖尿病患者在全身关键组织中的伤口愈合方面存在缺陷。在心脏中，糖尿病会诱导心肌纤维化，导致收缩功能受损，最终导致心力衰竭。众所周知，糖尿病患者在心肌梗死（MI）后生存率降低，其机制尚不清楚。心肌通过激活对这种损伤的特异性细胞反应来适应缺血诱导的梗死。心脏成纤维细胞（CF）和肌成纤维细胞是心肌修复的关键介质，并且在MI后急性活跃以稳定梗死区域并限制缺血损伤的程度。确定导致糖尿病伤口愈合受限、纤维化增加和MI恢复不良的机制是本提案的总体目标。将重点关注肌成纤维细胞，过度分泌的成纤维细胞表型，是急性损伤后伤口愈合所必需的。我们最近在1型糖尿病大鼠模型中确定，糖尿病心肌在基础（未受伤）状态下含有显著减少的心肌成肌纤维细胞，这使我们假设成肌纤维细胞的减少降低了心肌对MI的伤口愈合能力。我们提出这项建议的具体目标是：1）确定葡萄糖升高的影响（和胰岛素抵抗）对心肌成肌纤维细胞分化的影响，2）确定成肌纤维细胞含量是否以及在多大程度上有助于糖尿病心脏中的梗死后重构和功能的缺陷，和3）确定在梗死的糖尿病心肌的缺血区中直接注射成肌纤维细胞是否将加速糖尿病心肌的梗死后重构和功能。MI伤口愈合导致心脏功能改善。这些研究可以确定新的治疗靶点，为糖尿病心肌病的治疗开辟新的途径。 公共卫生相关性：糖尿病患者患有心血管并发症，包括高胆固醇、动脉粥样硬化和心脏病发作（或心肌梗死; MI）后死亡风险增加，尽管这些并发症的根本原因，特别是MI后死亡率增加的原因还没有很好地确定。我们认为，高死亡率可能与肌成纤维细胞的缺陷直接相关，肌成纤维细胞是专门的伤口愈合细胞，对身体几乎每个主要器官的伤口愈合和修复至关重要。该提案旨在了解糖尿病期间MI后恢复不良的基本机制，并确定预防和治疗这种疾病的潜在新途径。

DESCRIPTION (provided by applicant): Diabetic patients suffer from several cardiovascular complications that include hyperlipidemia, atherosclerosis, increased risk for myocardial infarction (MI) and declined global cardiac function. It is also recognized that diabetics have deficits in wound healing in key tissues throughout the body. In the heart, diabetes induces myocardial fibrosis leading to impaired contractile function and eventually, heart failure. Diabetic patients are also well known to have reduced survival rates following myocardial infarction (MI), the mechanisms that underlie this are not clear. The myocardium adapts to ischemia-induced infarction by activating specific cellular responses to this injury. Cardiac fibroblasts (CFs) and myofibroblasts are the critical mediators of myocardial repair, and are acutely active following MI to stabilize the infarcted area and limit the extent of the ischemic injury. Determining the mechanisms that cause limitations in diabetic wound healing, increased fibrosis, and poor recovery from MI are the overall goals of this proposal. Significant focus will be given to myofibroblasts, the hypersecretory fibroblastic phenotype that is essential for proper wound healing following acute injury. We have recently determined in a type 1 diabetic rat model that the diabetic myocardium contains significantly reduced numbers of cardiac myofibroblasts in the basal (uninjured) state, leading us to hypothesize that this reduction in myofibroblasts decreases the wound healing ability of the myocardium in response to MI. Our specific aims for this proposal are 1) to determine the effects of elevated glucose (and insulin resistance) on cardiac myofibroblast differentiation 2) to determine whether and to what extent the myofibroblast content contributes to deficits n post-infarction remodeling and function in the diabetic heart and 3) to determine whether direct injection of myofibroblasts in the ischemic zone of the infarcted diabetic myocardium will accelerate post-MI wound healing leading to improved cardiac function. These studies could identify new therapeutic targets and open new avenues for treatment of diabetic cardiomyopathy. PUBLIC HEALTH RELEVANCE: Diabetic patients suffer from cardiovascular complications that include high cholesterol, atherosclerosis, and increased risk of death following a heart attack (or myocardial infarction; MI), although the underlying causes of these complications, particularly the increased mortality post-MI, are not well defined. We believe that the high mortality rate may be directly related to a deficit in myofibroblasts, which are specialized wound healing cells that are critical for wound healing and repair in nearly every major organ in the body. This proposal aims to understand the basic mechanisms that underlie the poor post-MI recovery during diabetes and identify potential new avenues for the prevention and treatment of this disease.