Cardioprotective Effects of PDE-5 Inhibitors

PDE-5 抑制剂的心脏保护作用

基本信息

批准号：
8206609
负责人：
Rakesh C Kukreja
金额：
$ 44.05万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206609
关键词：
Adenosine Animal Model Apoptosis Apoptotic Atherosclerosis Attenuated Bayer brand of vardenafil hydrochloride Biological Availability Blood Vessels Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cell Death Cell model Chronic Cialis Clinical Trials Cyclic GMP Cyclic GMP-Dependent Protein Kinases DNA Binding Development Diabetes Mellitus Diabetic mouse Doxorubicin Endothelium Erectile dysfunction Fasting Functional disorder Gene Expression Gene Transfer Generations Glucose Guanylate Cyclase Heart Heart Hypertrophy Heart failure Human Hydrolysis Hyperglycemia Impairment Injury Insulin Insulin Resistance Investigation Ischemic Preconditioning Knowledge Lead MAPK8 gene Mediator of activation protein Metabolic Diseases Molecular Mus Muscle Myocardial Infarction NADPH Oxidase Nitric Oxide Nitric Oxide Signaling Pathway Non-Insulin-Dependent Diabetes Mellitus Obesity Oryctolagus cuniculus Oxidative Stress Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Population Process Production Pulmonary Edema Reperfusion Injury Role Sclerosis Signal Pathway Signal Transduction Sildenafil citrate Soluble Guanylate Cyclase Tenuate Testing Therapeutic Effect Vasodilation Viagra Xanthine Oxidase acute coronary syndrome base cardiovascular risk factor cytokine db/db mouse diabetic diabetic cardiomyopathy diabetic patient glucose uptake improved in vivo inhibitor/antagonist innovation insight men mitochondrial K(ATP) channel nitrosative stress novel overexpression phosphodiesterase V prevent protective effect public health relevance receptor-mediated signaling sildenafil tadalafil tool vardenafil vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Our innovative studies during the past 7 years have shown that potent phosphodiesterase-5 (PDE-5) inhibitors including sildenafil citrate (Viagra(R)) induce powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in various animal and cellular models. The purpose of this competing renewal application is to further demonstrate the therapeutic effect of these drugs against myocardial infarction (MI)-induced heart failure and insulin resistance in diabetic mice. We will test the following new hypotheses: 1: Modulation of cGMP with PDE-5 inhibitors and novel soluble guanylate cyclase (sGC) activator protect against myocardial infarction, apoptosis, remodeling and insulin resistance in the db/db diabetic mouse. We will determine the efficacy of short acting (sildenafil) or long acting (tadalafil) PDE-5 inhibitors and a novel sGC activator, BAY 58-2667 in protecting the diabetic heart and cardiomyocytes against myocardial infarction, apoptosis, contractile dysfunction, cardiac hypertrophy, pulmonary edema following I/R injury. 2: PDE-5 inhibitors/ sGC activator decrease oxidative stress and attenuate the expression of proinflammatory cytokines post MI in diabetic mice. 3: cGMP dependent protein kinases PKGI1 and 2 directly protect the diabetic heart through signaling mechanism involving activation of PI3K/Akt, AMPK, and inhibition of JNK and GSK- 32. These studies will be the first to demonstrate the protective effect of PDE-5 inhibitors and novel sGC activator in protection against post MI-induced heart failure in diabetic mice. We anticipate that results of these investigations will provide novel insights into expanding the utility of the cGMP preserving/generating compounds for treatment of diabetic cardiomyopathy. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are two of the most prevalent metabolic disorders in the world. Type II diabetes is associated with insulin resistance and increased myocardial infarction in both animal models and patients. In this proposal, we will study a new strategy for the protection of the heart and treatment of insulin resistance in Type II diabetic mice with erectile dysfunction drugs (Viagra(R) and Cialis(R)) and a novel drug BAY 58 2667 which produces cGMP - a potent muscle relaxing molecule in the body. We believe that knowledge derived from these studies will provide additional tools to the cardiologists in reducing damage of the heart following a heart attack and treatment of heart failure in diabetic patients. Moreover, our studies will help understand the molecular basis of the protection with these drugs.

描述（由申请人提供）：我们在过去7年中的创新研究表明，包括西地那非柠檬酸西地那非（伟哥（R））有效的磷酸二酯酶5（PDE-5）抑制剂会诱导针对凝血性再灌注损伤的强大心脏保护作用（I/R ）在各种动物和细胞模型中。这种竞争性更新应用的目的是进一步证明这些药物对糖尿病小鼠中心肌梗死（MI）诱导的心力衰竭和胰岛素抵抗的治疗作用。我们将测试以下新假设：1：用PDE-5抑制剂和新型可溶性鸟烯酸环化酶（SGC）激活剂对DB/DB糖尿病小鼠的抗心肌梗死，凋亡，重塑和胰岛素抵抗的调节。我们将确定短作用（西地那非）或长作用（tadalafil）PDE-5抑制剂的功效和新型SGC激活剂，Bay 58-2667在保护糖尿病心脏和心脏手肌细胞免受心肌梗死，凋亡，凋亡，收缩，心脏功能障碍，心脏功能障碍，心脏衰减，心脏超含量，心脏衰减，，，心脏过度，，心脏超级疾病，，，心脏不适，心脏功能障碍（ I/R损伤后的肺水肿。 2：PDE-5抑制剂/ SGC激活剂减少氧化应激，并减轻糖尿病小鼠MI后促炎细胞因子的表达。 3：CGMP依赖性蛋白激酶PKGI1和2通过涉及PI3K/AKT，AMPK激活以及JNK和GSK-32抑制的信号传导机制直接保护糖尿病心脏。这些研究将是首次证明PDE-5的保护作用抑制剂和新型SGC激活剂可防止MI诱导的糖尿病小鼠心力衰竭。我们预计这些研究的结果将为扩展CGMP保存/生成化合物的效用提供新的见解，以治疗糖尿病心肌病。公共卫生相关性：肥胖和2型糖尿病是世界上最普遍的两种代谢疾病。 II型糖尿病与动物模型和患者的胰岛素抵抗和心肌梗死有关。在该提案中，我们将研究一种新的策略，用于使用勃起功能障碍药物（伟哥（R）和Cialis（R））和新型药物Bay 58 2667中II型糖尿病小鼠的胰岛素抵抗治疗CGMP-体内有效的肌肉放松分子。我们认为，从这些研究中得出的知识将为心脏病专家提供其他工具，以减少心脏病发作和糖尿病患者心力衰竭的治疗后心脏病的损害。此外，我们的研究将有助于了解这些药物保护的分子基础。