Mechanism of Myocardial Reperfusion Injury in Diabetes

描述（由申请人提供）：与非糖尿病患者相比，糖尿病患者在初次心肌梗死后的死亡风险较高，心肌梗死仍然是糖尿病患者的主要死因。糖尿病患者中与心肌梗死相关的死亡风险增加被认为部分是由于心肌梗死面积增加。内皮型一氧化氮合酶（eNOS）衍生的NO对心肌缺血再灌注（MI-R）损伤具有保护作用，并且eNOS衍生的NO在2型糖尿病患者中显著减弱。eNOS衍生的NO减少可能有助于糖尿病患者心肌梗死的严重程度增加。关于eNOS和NO在糖尿病心肌MI-R损伤中的作用的信息很少。初步数据表明，NO供体减弱了db/db糖尿病小鼠中的MI-R损伤。拟议的研究将检查使用NO供体和eNOS腺病毒的心脏特异性gone治疗来保护糖尿病心肌免受MI-R损伤。我们还将在一种新的eNOS转基因/db/db糖尿病双突变小鼠模型中研究MI-R损伤。此外，在本资助申请中提出的研究将检查在db/db糖尿病小鼠中MI-R后NO治疗的心脏保护作用的机制。所提出的研究将检查血红素加氧酶和可溶性鸟苷酸环化酶信号通路在糖尿病中NO介导的心脏保护中的作用。本研究将探讨一氧化碳（CO）、环鸟苷酸（cGMP）、cGMP依赖性蛋白激酶（PKG）、p38丝裂原活化蛋白激酶（p38 MAPK）和线粒体ATP敏感性K+通道（mitOKATp）在NO介导的糖尿病心肌保护中的作用。 拟议研究的具体目标是： 具体目标1：目的探讨一氧化氮（NO）在糖尿病心肌缺血再灌注损伤中的作用。 具体目标2：观察一氧化氮（NO）治疗对糖尿病心肌再灌注损伤时HO-1活性的影响及心肌保护作用。 具体目标#3：探讨NO治疗对糖尿病心肌再灌注损伤中可溶性鸟苷酸环化酶（sGC）的刺激作用和心肌保护作用，为糖尿病心肌再灌注损伤的复杂病理生理机制提供新的认识。这项资助计划中的研究还将检查各种形式的NO治疗（NO供体和Gone治疗）在糖尿病MI-R损伤中的疗效。最后，这些研究将提供新的见解，负责NO介导的糖尿病心脏保护的细胞机制。

DESCRIPTION (provided by applicant): Diabetic patients have a higher risk of mortality following an initial myocardial infarction when compared to nondiabetics and myocardial infarction remains the principal cause of death in patients with diabetes mellitus. The increased risk of mortality associated with myocardial infarction in diabetics is believed to be due in part to an increased size of myocardial infarction. Endothelial nitric oxide synthase (eNOS) derived NO protects against myocardial ischemia-reperfusion (MI-R) injury and eNOS-derived NO is markedly attenuated in persons with type 2 diabetes mellitus. Reductions in eNOS-derived NO may contribute to the enhanced severity of myocardial infarction in diabetics. A paucity of information exists regarding the role of eNOS and NO in the diabetic myocardium in the setting of MI-R injury. Preliminary data indicates that NO donors attenuate MI-R injury in the db/db diabetic mouse. Proposed studies will examine the use of NO donors and cardiac-specific gone therapy with eNOS adenoviruses to protect the diabetic myocardium against MI-R injury. We will also examine MI-R injury in a novel eNOS transgenic/db/db diabetic double mutant mouse model. Furthermore, studies proposed in this grant application will examine the mechanisms responsible for the cardioprotective actions of NO therapy following MI-R in the db/db diabetic mouse The proposed studies will examine the role(s) of both the heme oxygenase and soluble guanylate cyclase signaling pathways in NO-mediated cardioprotection in diabetes. The studies will address a number of downstream signaling components including: carbon monoxide (CO), cyclic guanosine-3', 5'-monophosphate (cGMP), cGMP-dependent protein kinase (PKG), p38 mitogen activated protein kinase (p38 MAPK), andmitochondrial ATP-sensitive K+ channels (mitOKATp) in NO-mediated protection of the diabetic myocardium. The specific aims of the proposed studies are: Specific Aim # 1: To investigate the effects of nitric oxide (NO) therapy in the setting of myocardialischemia-reperfusion injury in the diabetic heart. Specific Aim # 2: To examine the effects of NO therapy on home oxygenase-1 (HO-1) activation and myocardial protection in the setting of myocardial reperfusion injury in the diabetic heart. Specific Aim # 3: To examine the effects of NO therapy on soluble guanylate cyclase (sGC) stimulation and myocardial protection in the setting of myocardial reperfusion injury in the diabetic heart.The proposed studies will provide novel insights regarding the complex pathophysiology of myocardial reperfusion injury in the diabetic myocardium. Studies proposed in this grant will also examine the efficacy of various forms of NO therapy (NO donors and gone therapy) in the setting of MI-R injury in diabetes mellitus. Finally, these studies will provide novel insights into the cellular mechanisms responsible for NO-mediated cardioprotection in diabetes.