Cardioprotective Effects of PDE-5 Inhibitors

描述(申请人提供)：我们在过去7年中的创新研究表明，包括柠檬酸西地那非(Viagra(R))在内的有效的磷酸二酯酶-5(PDE-5)抑制剂在各种动物和细胞模型中都能对缺血再灌注损伤(I/R)产生强大的心脏保护作用。这一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)引起的心力衰竭和胰岛素抵抗的治疗效果。我们将验证以下新假设：1：PDE-5抑制剂和新型可溶性鸟苷环化酶(SGC)激动剂对cGMP的调节对db/db糖尿病小鼠的心肌梗死、细胞凋亡、重构和胰岛素抵抗具有保护作用。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激动剂Bay 58-2667在保护糖尿病心脏和心肌细胞免受心肌梗死、细胞凋亡、收缩功能障碍、心肌肥厚和I/R损伤后肺水肿方面的有效性。2：PDE-5抑制剂/sGC激活剂可减轻糖尿病小鼠心肌梗死后氧化应激，减轻促炎细胞因子的表达。3：cGMP依赖的蛋白激酶PKGI1和2通过激活PI3K/Akt、AMPK、抑制JNK和GSK-32等信号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激动剂对糖尿病小鼠心肌梗死后心力衰竭的保护作用。我们预计，这些研究的结果将为扩大cGMP保存/生成化合物用于治疗糖尿病心肌病的效用提供新的见解。 公共卫生相关性：肥胖和2型糖尿病是世界上最常见的两种代谢紊乱。在动物模型和患者中，II型糖尿病与胰岛素抵抗和心肌梗死增加有关。在这项提案中，我们将研究一种新的策略，用于保护患有勃起功能障碍的II型糖尿病小鼠的心脏和治疗胰岛素抵抗，药物包括伟哥(Viagra(R)和Cialis(R))和新药Bay 58 2667，这种新药可以在体内产生一种有效的肌肉松弛分子--cGMP。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害和治疗糖尿病患者的心力衰竭。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.