ROS, Inflammation, and Cardioprotection in Type 2 Diabetes

2 型糖尿病中的 ROS、炎症和心脏保护

• 批准号: 8701394
• 负责人: Rakesh C Kukreja
• 金额: $ 49.36万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701394
• 关键词: Advanced Glycosylation End Products; American; Antioxidants; Apoptosis; Atherosclerosis; Attenuated; Bayer brand of vardenafil hydrochloride; Biological Availability; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Caspase-1; Cell Death; Cerebrovascular Disorders; Chronic; Cialis; Clinical Research; Coronary Arteriosclerosis; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Depressed mood; Development; Diabetes Mellitus; Diet; Disease; Dominant-Negative Mutation; Doxorubicin; Enzymes; Erectile dysfunction; Event; Fatty acid glycerol esters; Functional disorder; Generations; Glutathione S-Transferase; Goals; Heart; Heart Diseases; Heart failure; Hyperglycemia; Hypertrophy; Impairment; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Insulin; Insulin Resistance; Ischemia; Kidney Diseases; Knockout Mice; Laboratories; Lead; Lipids; Mitochondria; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Necrosis; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Oxidative Stress; Patients; Pharmacotherapy; Phosphorylation; Play; Population; Prevalence; Prevention; Property; Reperfusion Injury; Reperfusion Therapy; Respiratory Chain; Retinal Diseases; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Transgenic Mice; United States; United States Food and Drug Administration; Vascular Endothelium; Viagra; acute coronary syndrome; attenuation; base; cytokine; design; diabetic; diabetic patient; endothelial dysfunction; feeding; inhibitor/antagonist; innovation; mortality; novel; overexpression; painful neuropathy; pandemic disease; phosphodiesterase V; preclinical study; prevent; protective effect; public health relevance; pulmonary arterial hypertension; sildenafil; tadalafil; vardenafil; vascular inflammation

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is rapidly becoming a global pandemic and is projected to afflict more than 300 million individuals worldwide by the year 2025. This disease constitutes a major independent risk factor for heart attack and myocardial cell death. The current lines of drug therapy are insufficient to control this devastating disease and its serious cardiovascular complications. Based on our ample preliminary data, the current project is designed to test the following central HYPOTHESIS: Chronic inhibition of phosphodiesterase-5 (PDE-5) protects T2D hearts through suppression of myocardial oxidative stress and inflammasome formation via the AMPK/Sirt1/PGC-1¿ signal transduction network that leads to induction of mitochondrial antioxidant enzyme - glutathione S-transferase kappa 1 (GSTK1) and improvement of mitochondrial function. We propose the following 3 specific aims. Aim 1: PDE-5 inhibition with tadalafil activates AMPK/Sirt1/PGC-1¿ signaling pathway and attenuates cell death (necrosis/apoptosis) and mitochondrial respiratory chain dysfunction following myocardial ischemia/reperfusion (I/R) in T2D. Using db/db and high fat diet (HFD)-fed T2D mice, we will demonstrate the effect of tadalafil treatment on a) AMPK phosphorylation, eNOS and nitric oxide generation; b) the possible loss of cardioprotection in the AMPK¿2 dominant negative transgenic mice following I/R; c) the role of AMPK in activating Sirt1 and PGC-1¿; and d) the potential interplay of cGMP-dependent protein kinase (PKG) and AMPK/Sirt1/PGC-1¿ signal transduction network in attenuation of cardiomyocyte apoptosis/necrosis and mitochondrial respiratory chain dysfunction following I/R. Aim 2: PDE-5 inhibition restores depressed level of mitochondrial GSTK1 in the T2D hearts and attenuates I/R injury via its antioxidant as well as lipid-regulating properties. Using GSTK1 knockout mice with HFD-induced T2D, we will demonstrate the causative role of GSTK1 in PDE-5 inhibitor-induced cardioprotection and lipid regulating properties in T2D. We will also induce targeted overexpression of GSTK1 by direct intramyocardial injection of adenoviral GSTK1 to demonstrate the direct cause and effect relationship of GSTK1 in reducing I/R injury in T2D hearts. Aim 3: PDE-5 inhibitors attenuate inflammation through suppression of inflammasome and inhibition of caspase-1 in diabetic heart. We will examine: a) the role of PDE-5 inhibitors in attenuating inflammosome formation with consequent inhibition of caspase-1 activity following I/R in the heart and cardiomyocytes; b) the role of AMPK and Sirt-1 in attenuation of inflammasome formation; c) the involvement of AMPK, GSTK1, and PKG1¿ in prevention of inflammasome formation following I/R. Overall, the proposed studies will pave the way to a potentially novel pharmacotherapy against inflammation and cardiac injuries resulting from T2D conditions.

描述（由申请人提供）：2型糖尿病（T2 D）正在迅速成为全球大流行病，预计到2025年全球将有超过3亿人患病。这种疾病构成了心脏病发作和心肌细胞死亡的主要独立危险因素。目前的药物治疗线不足以控制这种毁灭性的疾病及其严重的心血管并发症。基于我们丰富的初步数据，本项目旨在验证以下中心假设：磷酸二酯酶-5（PDE-5）的慢性抑制通过AMPK/Sirt 1/PGC-1抑制心肌氧化应激和炎性小体形成来保护T2 D心脏。导致诱导线粒体抗氧化酶-谷胱甘肽S-转移酶κ 1（GSTK 1）的信号转导网络和线粒体功能的改善。我们提出以下三个具体目标。目标1：他达拉非抑制PDE-5可激活AMPK/Sirt 1/PGC-1？信号通路，减轻T2 D患者心肌缺血/再灌注（I/R）后的细胞死亡（坏死/凋亡）和线粒体呼吸链功能障碍。使用db/db和高脂饮食（HFD）喂养的T2 D小鼠，我们将证明他达拉非治疗对a）AMPK磷酸化、eNOS和一氧化氮生成的影响; B）I/R后AMPK 2显性阴性转基因小鼠心脏保护的可能丧失; c）AMPK在激活Sirt 1和PGC-1中的作用; cGMP依赖性蛋白激酶（PKG）和AMPK/Sirt 1/PGC-1 <$信号转导网络在减轻I/R后心肌细胞凋亡/坏死和线粒体呼吸链功能障碍中的潜在相互作用。目标二：PDE-5抑制恢复T2 D心脏中线粒体GSTK 1的降低水平，并通过其抗氧化剂和调脂特性减轻I/R损伤。使用GSTK 1敲除小鼠HFD诱导的T2 D，我们将证明GSTK 1在PDE-5通道诱导的心脏保护和T2 D中的脂质调节特性中的致病作用。我们还将通过直接心肌内注射腺病毒GSTK 1来诱导GSTK 1的靶向过表达，以证明GSTK 1在减少T2 D心脏I/R损伤中的直接因果关系。目的3：PDE-5抑制剂通过抑制炎性小体和caspase-1的表达减轻糖尿病心脏的炎症反应。我们将研究：a）PDE-5抑制剂在减轻心脏和心肌细胞I/R后炎性小体形成中的作用，从而抑制caspase-1活性; B）AMPK和Sirt-1在减轻炎性小体形成中的作用; c）AMPK、GSTK 1和PKG 1？参与预防I/R后炎性小体形成。总体而言，拟议的研究将为针对T2 D疾病引起的炎症和心脏损伤的潜在新型药物治疗铺平道路。