Therapeutic Approaches for Treatment of Diabetic Complications of Heart and Vascular Diseases

糖尿病心脏和血管疾病并发症的治疗方法

• 批准号: 9351979
• 负责人: Edward Lakatta
• 金额: $ 7.67万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9351979
• 关键词: 5' -AMP-activated protein kinase; Acute; Advanced Glycosylation End Products; Age; Amputation; Animal Model; Apolipoprotein E; Attenuated; Bolus Infusion; Breeding; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Complications of Diabetes Mellitus; Coronary; Coronary artery; Cytoplasmic Granules; Data; Development; Diabetes Mellitus; Diabetic Foot; Disease; Experimental Models; Glucose; Goals; Heart; Heart Diseases; Heart failure; Hyperglycemia; Injection of therapeutic agent; Injury; Insulin; Intake; Ischemia; Kidney Diseases; Knock-in; Knockout Mice; Ligands; Ligation; Limb structure; Measures; Mediating; Metabolic Diseases; Metabolism; Modality; Morbidity - disease rate; Mouse Strains; Myocardial; Myocardial Infarction; Myocardial Ischemia; Patients; Peripheral arterial disease; Population; Prevention; Quality of life; Rattus; Regulation; Role; Saline; Signal Transduction; Streptozocin; System; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Vascular Diseases; Ventricular Dysfunction; desensitization; diabetic; diabetic cardiomyopathy; diabetic patient; femoral artery; glucose metabolism; heart metabolism; improved; mortality; novel; novel therapeutic intervention; pre-clinical; prevent; programs; receptor; receptor for advanced glycation endproducts; response; sensor

The broad objective of this program is to perform preclinical experimentation on animal models of diabetes with myocardial ischemia and subsequent CHF or with hind limb ischemia to elucidate the mechanisms of diabetic cardiomyopathy and peripheral artery diseases to evaluate the potential of different therapeutic modalities to prevent or attenuate the development of CHF and diabetic foot in diabetic patients. I. AMP-activated Protein Kinase (AMPK) in Regulation of Cardiac Metabolism and Function in Diabetes Diabetic cardiomyopathy is a deadly ventricular dysfunction caused by abnormal glucose metabolism in diabetic patients. AMPK is, as a major energy sensor, responsible for glucose metabolism in heart. Hence, the roles of AMPK mechanism in diabetic cardiomyopathy are not completely clear. The goal of this project is to elucidate the role of AMPK in hyperglycemic damage to the heart and its relationship with insulin desensitization in cardiomyocytes. Specific aims are: 1) the changes in AMPK activity in response to hyperglycemia; 2) the role in insulin desensitization and formation of glucose granules in diabetic hearts; and 3) whether manipulations of AMPK or subtypes can improve glucose intake and metabolism. For this purpose, we start to breed transgenic AMPK gamma2 subunit knock-in and knock-out mouse strains in our lab. Those transgenic mouse strains and their respective wild-type counterparts will be subjected to coronary artery ligation or femoral artery ligation after they developed diabetes through STZ injections. Upon completion of this project, it will provide novel targets in AMPK signaling system that can be pharmacologically manipulated for prevention and treatment of diabetic complications of heart and vascular diseases. II. The receptor for advanced glycation end-products (RAGE) RAGE and its soluble forms of RAGE (sRAGE) are the emerging mechanisms that involve in the pathobiology of a wide range of diseases including cardiovascular diseases and diabetes. Hence, the role of sRAGE in diabetic cardiomyopathy and diabetic limb diseases are not clear. Experimental data suggest that sRAGE may neutralize the ligand-mediated damage by acting as a decoy. We tested whether sRAGE is cardio protective against myocardial acute ischemic injury. In an experimental model of myocardial infarction induced by permanent ligation of a coronary artery in rats, a single bolus injection of 1ug/kg of sRAGE immediately after coronary ligation, reduced myocardial infarction (MI) measured 24 h after coronary ligation by 50% compared to saline injection. For this purpose, we start to breed transgenic sRAGE+/RAGE- mouse strain and its cross-breed with ApoE-/- transgenic mouse which is prone to develop aortic aneurism, in our lab. Those transgenic mouse strains and their respective wild-type counterparts will be subjected to coronary artery ligation or femoral artery ligation after they developed diabetes through STZ injections. Upon completion of this project, it will provide proof of concept that sRAGE can be used for prevention and treatment of diabetic complications of heart and vascular diseases.

The broad objective of this program is to perform preclinical experimentation on animal models of diabetes with myocardial ischemia and subsequent CHF or with hind limb ischemia to elucidate the mechanisms of diabetic cardiomyopathy and peripheral artery diseases to evaluate the potential of different therapeutic modalities to prevent or attenuate the development of CHF and diabetic foot in diabetic patients. I.在心脏代谢和糖尿病功能的调节中，AMP激活的蛋白激酶（AMPK） 糖尿病心肌病是糖尿病患者异常葡萄糖代谢引起的一种致命的心室功能障碍。作为主要能量传感器，AMPK是负责心脏葡萄糖代谢的主要能量传感器。因此，AMPK机制在糖尿病心肌病中的作用尚不完全清楚。该项目的目的是阐明AMPK在心脏高血糖损害中的作用及其与心肌细胞中胰岛素脱敏的关系。 具体目的是：1）响应高血糖的AMPK活性的变化； 2）在糖尿病心脏中葡萄糖颗粒的胰岛素脱敏和形成中的作用； 3）AMPK或亚型的操纵是否可以改善葡萄糖摄入和代谢。为此，我们开始在实验室中繁殖转基因AMPK GAMMA2亚基敲入和敲除小鼠菌株。那些转基因小鼠菌株及其各自的野生型对应物将在通过STZ注射患糖尿病后进行冠状动脉连接或股动脉连接。该项目完成后，它将在AMPK信号系统中提供新的靶标，可以在药理上操纵以预防和治疗心脏和血管疾病的糖尿病并发症。 ii。晚期糖基化终产物（愤怒）的受体 愤怒及其可溶性的愤怒形式（Srage）是涉及各种疾病的病理生物学的新兴机制，包括心血管疾病和糖尿病。因此，SRAGE在糖尿病心肌病和糖尿病肢体疾病中的作用尚不清楚。 实验数据表明，SRAGE可以通过充当诱饵来中和配体介导的损伤。我们测试了Srage是否具有心肌急性缺血性损伤是有氧保护性的。在大鼠冠状动脉永久连接诱导的心肌梗塞的实验模型中，冠状动脉结扎后立即注射1ug/kg Srage的单块SRAGE，在冠状结扎术后24小时降低了50％的冠状动脉结扎后心肌梗塞（MI）。为此，我们开始在我们的实验室中繁殖转基因SRAGE+/RAGE小鼠菌株，并与ApoE - / - 转基因小鼠交叉繁殖，该小鼠容易发展为主动脉动脉瘤。那些转基因小鼠菌株及其各自的野生型对应物将在通过STZ注射患糖尿病后进行冠状动脉连接或股动脉连接。该项目完成后，它将提供概念证明，即SRAGE可用于预防和治疗心脏和血管疾病的糖尿病并发症。