ROS, Inflammation, and Cardioprotection in Type 2 Diabetes

2 型糖尿病中的 ROS、炎症和心脏保护

基本信息

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
项目类别：
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

项目摘要

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 (T2D) 正在迅速成为全球流行病，预计到 2025 年将影响全球超过 3 亿人。这种疾病是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不足以控制这种毁灭性的疾病及其严重的心血管并发症。根据我们充足的初步数据，当前的项目旨在检验以下中心假设：慢性抑制磷酸二酯酶 5 (PDE-5) 可通过 AMPK/Sirt1/PGC-1 抑制心肌氧化应激和炎症小体形成，从而保护 T2D 心脏诱导线粒体抗氧化酶 - 谷胱甘肽 S-转移酶 kappa 1 (GSTK1) 和改善线粒体功能的信号转导网络我们提出以下 3 个具体目标：他达拉非抑制 PDE-5 激活 AMPK/Sirt1/PGC。 -1¿我们将使用 db/db 和高脂饮食 (HFD) 喂养的 T2D 小鼠来证明其效果。他达拉非治疗对 a) AMPK 磷酸化、eNOS 和一氧化氮生成的影响；b) 心脏保护作用可能丧失； AMPK?? 2 只 I/R 后显性失活转基因小鼠；c) AMPK 在激活 Sirt1 和 PGC-1 中的作用¿ d) cGMP 依赖性蛋白激酶 (PKG) 和 AMPK/Sirt1/PGC-1¿信号转导网络在 I/R 后减轻心肌细胞凋亡/坏死和线粒体呼吸链功能障碍中的作用目标 2：PDE-5 抑制可恢复 T2D 心脏中线粒体 GSTK1 的低水平，并通过其抗氧化剂和脂质减轻 I/R 损伤。 -使用 GSTK1 敲除小鼠进行 HFD 诱导的 T2D，我们将证明 GSTK1 在 PDE-5 抑制剂诱导的心脏保护中的致病作用。我们还将通过直接心肌内注射腺病毒 GSTK1 诱导 GSTK1 的靶向过度表达，以证明 GSTK1 在减少 T2D 心脏 I/R 损伤方面的直接因果关系目标 3：PDE-5 抑制剂减弱。通过抑制炎症小体和抑制 caspase-1 来抑制糖尿病心脏的炎症我们将检查：a) PDE-5 抑制剂在糖尿病心脏中的作用。减弱心脏和心肌细胞 I/R 后炎症小体的形成，从而抑制 caspase-1 活性；b) AMPK 和 Sirt-1 在减弱炎症小体形成中的作用；c) AMPK、GSTK1 和 PKG1 的参与；总体而言，拟议的研究将为针对 T2D 病症引起的炎症和心脏损伤的潜在新型药物疗法铺平道路。