Cardioprotective Effects of PDE-5 Inhibitors

描述（由申请人提供）：我们在过去7年的创新研究表明，在各种动物和细胞模型中，有效的磷酸二酯酶-5 （PDE-5）抑制剂，包括枸橼酸西地那非（伟哥），对缺血再灌注损伤（I/R）具有强大的心脏保护作用。这项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。我们将验证以下新的假设：1:PDE-5抑制剂和新型可溶性鸟苷酸环化酶（sGC）激活剂调节cGMP对db/db糖尿病小鼠心肌梗死、细胞凋亡、重塑和胰岛素抵抗有保护作用。我们将确定短效（西地那非）或长效（他达拉非）PDE-5抑制剂和一种新型sGC激活剂BAY 58-2667在I/R损伤后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、心脏肥厚和肺水肿的功效。2: PDE-5抑制剂/ sGC激活剂降低糖尿病小鼠心肌梗死后氧化应激，降低促炎细胞因子的表达。3: cGMP依赖性蛋白激酶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激活剂对心肌梗死后糖尿病小鼠心力衰竭的保护作用。我们预计这些研究结果将为扩大cGMP保存/生成化合物在糖尿病性心肌病治疗中的应用提供新的见解。

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.