Mechanism of Myocardial Reperfusion Injury in Diabetes

描述（由申请人提供）：与非糖尿病患者相比，糖尿病患者在初始心肌梗死后死亡的风险更高，心肌梗死仍然是糖尿病患者死亡的主要原因。糖尿病患者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的大小增加。内皮型一氧化氮合酶（eNOS）衍生的NO对心肌缺血-再灌注（MI-R）损伤有保护作用，2型糖尿病患者eNOS衍生的NO明显减弱。enos源性NO的减少可能有助于糖尿病患者心肌梗死严重程度的增强。关于心肌缺血再灌注损伤时eNOS和NO在糖尿病心肌中的作用，目前还缺乏相关信息。初步数据表明，NO供体可减轻db/db糖尿病小鼠的MI-R损伤。拟议的研究将检验使用NO供体和心脏特异性的eNOS腺病毒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检测MI-R损伤。此外，本拨款申请中提出的研究将研究在db/db糖尿病小鼠MI-R后NO治疗的心脏保护作用机制。拟议的研究将研究血红素加氧酶和可溶性鸟苷酸环化酶信号通路在NO介导的糖尿病心脏保护中的作用。这些研究将解决一些下游信号成分，包括一氧化碳（CO）、环鸟苷-3′，5′-单磷酸（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K+通道（mitOKATp）在no介导的糖尿病心肌保护中的作用。

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.