Cardioprotective Effects of PDE-5 Inhibitors

描述（由申请人提供）：我们在过去7年中的创新研究表明，强效磷酸二酯酶-5（PDE-5）抑制剂（包括枸橼酸西地那非（Viagra（R）在各种动物和细胞模型中对缺血-再灌注损伤（I/R）产生强大的心脏保护作用。本次竞争性更新申请的目的是进一步证明这些药物对糖尿病小鼠心肌梗死（MI）诱导的心力衰竭和胰岛素抵抗的治疗作用。我们将测试以下新的假设：1：用PDE-5抑制剂和新型可溶性鸟苷酸环化酶（sGC）激活剂调节cGMP可保护db/db糖尿病小鼠免受心肌梗死、细胞凋亡、重塑和胰岛素抵抗。我们将确定短效（西地那非）或长效（他达拉非）PDE-5抑制剂和新型sGC激活剂BAY 58-2667在保护糖尿病心脏和心肌细胞免受I/R损伤后的心肌梗死、细胞凋亡、收缩功能障碍、心脏肥大、肺水肿方面的疗效。2：PDE-5抑制剂/ sGC激活剂降低糖尿病小鼠MI后氧化应激并减弱促炎细胞因子的表达。第三章：cGMP依赖性蛋白激酶PKGI 1和PKGI 2通过涉及PI 3 K/Akt、AMPK的活化以及JNK和GSK- 32的抑制的信号传导机制直接保护糖尿病心脏。这些研究将首次证明PDE-5抑制剂和新型sGC激活剂在糖尿病小鼠中对MI后诱导的心力衰竭的保护作用。我们预计，这些研究的结果将提供新的见解，扩大cGMP保护/生成化合物治疗糖尿病性心肌病的效用。 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紊乱。在动物模型和患者中，II型糖尿病与胰岛素抵抗和增加的心肌梗死相关。在这项提案中，我们将研究一种新的策略，用于保护心脏和治疗II型糖尿病小鼠的胰岛素抵抗，这些小鼠使用勃起功能障碍药物（Viagra（R）和Cialis（R））和一种新型药物BAY 58 2667，该药物产生cGMP -一种有效的肌肉松弛分子。我们相信，从这些研究中获得的知识将为心脏病专家提供额外的工具，以减少心脏病发作后的心脏损伤和糖尿病患者心力衰竭的治疗。此外，我们的研究将有助于了解这些药物保护的分子基础。

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.