Post-Infarction Remodeling in the Diabetic Myocardium

描述(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)风险增加和全球心功能下降。人们还认识到，糖尿病患者全身关键组织的伤口愈合存在缺陷。在心脏方面，糖尿病导致心肌纤维化，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)后存活率降低，其机制尚不清楚。心肌通过激活对这种损伤的特定细胞反应来适应缺血诱导的梗塞。心肌成纤维细胞(CFs)和肌成纤维细胞是心肌修复的重要介质，在心肌梗死后发挥着稳定心肌梗死面积、限制心肌缺血损伤的作用。确定导致糖尿病创面愈合受限、纤维化增加和心肌梗塞恢复不良的机制是这项提案的总体目标。重点将放在肌成纤维细胞，这是一种高分泌的成纤维细胞表型，对于急性损伤后正确的伤口愈合是必不可少的。我们最近在一种1型糖尿病大鼠模型中确定，糖尿病大鼠心肌中处于基础(未损伤)状态的心肌成纤维细胞数量显著减少，这导致我们假设心肌成纤维细胞的这种减少降低了心肌对MI的创伤修复能力。我们提出这一建议的具体目的是：1)确定血糖升高(和胰岛素抵抗)对心肌成纤维细胞分化的影响；2)确定肌成纤维细胞的含量是否以及在多大程度上导致糖尿病心脏梗死后重构和功能的缺陷；3)确定直接在糖尿病心肌梗死后缺血区注射肌成纤维细胞是否会加速心肌梗死后伤口的愈合，从而改善心功能。这些研究可以确定新的治疗靶点，并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，以及心脏病发作(或心肌梗死；MI)后死亡风险的增加，尽管这些并发症的潜在原因，特别是MI后死亡率的增加，尚未得到很好的定义。我们认为，高死亡率可能与肌成纤维细胞的缺陷直接相关，肌成纤维细胞是一种专门的伤口愈合细胞，对几乎身体每个主要器官的伤口愈合和修复都是至关重要的。这项建议旨在了解糖尿病期间心肌梗塞后恢复较差的基本机制，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.