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（由适用提供）：2型糖尿病（T2D）正迅速成为全球大流行，预计到2025年，全球超过3亿个人。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。当前的药物治疗线不足以控制这种毁灭性疾病及其严重的心血管并发症。基于我们充分的初步数据，当前的项目旨在测试以下中心假设：长期抑制磷酸二酯酶5（PDE-5）通过抑制心肌氧化应激和通过AMPK/SIRT1/pGC-1信号传递网络引起的诱导型MITCOCHICENTRIANE MITOCHENE的MITRIANE MITERE的粉刺型和炎症形成通过抑制心肌氧化应激和炎症形成来保护T2D心脏。 S-转移酶Kappa 1（GSTK1）和线粒体功能的改善。我们提出以下3个特定目标。 AIM 1：用他达拉非氨抑制PDE-5激活AMPK/SIRT1/PGC-1。信号通路，并减轻在T2D中心肌缺血/重复（I/R）后，在心肌症状（I/R）后，在心肌症状（I/R）后减轻细胞死亡（坏死/凋亡）和线粒体呼吸链功能障碍。使用DB/DB和高脂肪饮食（HFD）喂养的T2D小鼠，我们将证明他达拉非治疗对A）AMPK磷酸化，eNOS和一氧化氮产生的影响； b）在I/R之后，AMPK考有的2个显性负转基因小鼠可能会损失心脏保护； c）AMPK在激活SIRT1和PGC-1上的作用； d）CGMP依赖性蛋白激酶（PKG）和AMPK/SIRT1/PGC-1€的潜在相互作用在I/R之后的心肌细胞凋亡和线粒体呼吸链功能障碍的衰减中信号翻译网络。 AIM 2：PDE-5抑制作用恢复了T2D心脏中线粒体GSTK1的抑郁水平，并通过其抗氧化剂和脂质调节特性减轻I/R损伤。使用与HFD诱导的T2D的GSTK1基因敲除小鼠，我们将证明GSTK1在PDE-5抑制剂诱导的心脏保护和脂质调节特性中的病因作用。我们还将通过直接对腺病毒GSTK1的直接注射腺病毒GSTK1诱导靶向GSTK1的靶向过表达，以证明GSTK1在减少T2D心脏I/R损伤时GSTK1的直接原因和作用关系。 AIM 3：PDE-5抑制剂通过抑制炎性体和抑制糖尿病心脏中的caspase-1抑制剂。我们将检查：a）PDE-5抑制剂在减弱炎症体形成中的作用，并因此在心脏和心肌细胞中I/R后抑制caspase-1活性； b）AMPK和SIRT-1在炎症组形成衰减中的作用； c）在I/R之后，AMPK，GSTK1和PKG1的参与预防炎性体形成。总体而言，拟议的研究将为T2D疾病引起的炎症和心脏损伤的潜在新型药物疗法铺平道路。