Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms
Vasonatrin peptide attenuates myocardial ischemia-reperfusion injury in diabetic rats and underlying mechanisms
复制标题
Vasonatrin肽减轻糖尿病大鼠心肌缺血再灌注损伤及其机制
DOI：
10.1152/ajpheart.00666.2014
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发表时间：
2015-02-15
影响因子：
4.8
通讯作者：
Zhang, Haifeng
中科院分区：
文献类型：
--
作者：
Shi, Zhenwei;Fu, Feng;Zhang, Haifeng
糖尿病增加了缺血性心脏病的发病率/死亡率。尽管心钠素和C型利钠肽可减轻非糖尿病大鼠心肌缺血再灌注损伤，但心房利钠肽和C型利钠肽人工合成的嵌合体血管钠尿肽是否具有抗心肌缺血再灌注损伤的作用尚不清楚，尤其是对糖尿病大鼠。本研究旨在观察VNP对糖尿病大鼠缺血再灌注损伤的影响，并进一步阐明其作用机制。采用高脂饲料喂养的链脲佐菌素诱导的糖尿病SD大鼠进行缺血再灌注手术。静脉注射VNP(100 mg/kg，再灌流前10min)可显著提高左心室内压(+/-LV dp/dt(Max))和左心室收缩压的瞬时一阶导数(+/-LV dp/dt(Max))，降低左心室舒张末压、细胞凋亡指数、caspase-3活性、血浆肌酸激酶(CK)和乳酸脱氢酶(LDH)活性。此外，VNP通过抑制葡萄糖调节蛋白78(GRP78)和C/EBP同源蛋白(CHOP)来抑制内质网(ER)应激。这些作用可被cGMP类似物8-溴-环鸟苷磷酸(8-Br-cGMP)所模拟，但可被PKG选择性抑制剂KT-5823抑制。此外，预先给予内质网应激的特异性抑制剂牛磺熊去氧胆酸(TUDCA)不能进一步增强VNP对糖尿病大鼠的心脏保护作用。体外培养的H9c2心肌细胞在缺氧/复氧条件下，加入或不加入VNP(10(-8)mol/L)孵育。用siRNA敲除PKG1α基因可减弱VNP对内质网应激和细胞凋亡的抑制作用，而过表达PKG1α可显著降低内质网应激和细胞凋亡。VNP通过cGMP-PKG信号通路抑制内质网应激，保护糖尿病大鼠心脏免受缺血再灌注损伤。这些结果提示，VNP对糖尿病合并缺血性心脏病有潜在的治疗价值。
Diabetes mellitus increases morbidity/mortality of ischemic heart disease. Although atrial natriuretic peptide and C-type natriuretic peptide reduce the myocardial ischemia-reperfusion damage in nondiabetic rats, whether vasonatrin peptide (VNP), the artificial synthetic chimera of atrial natriuretic peptide and C-type natriuretic peptide, confers cardioprotective effects against ischemia-reperfusion injury, especially in diabetic patients, is still unclear. This study was designed to investigate the effects of VNP on ischemia-reperfusion injury in diabetic rats and to further elucidate its mechanisms. The high-fat diet-fed streptozotocin-induced diabetic Sprague-Dawley rats were subjected to ischemia-reperfusion operation. VNP treatment (100 mu g/kg iv, 10 min before reperfusion) significantly improved the instantaneous first derivation of left ventricle pressure (+/- LV dP/dt(max)) and LV systolic pressure and reduced LV end-diastolic pressure, apoptosis index, caspase-3 activity, plasma creatine kinase (CK), and lactate dehydrogenase (LDH) activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). These effects were mimicked by 8-bromine-cyclic guanosinemonophosphate (8-Br-cGMP), a cGMP analog, whereas they were inhibited by KT-5823, the selective inhibitor of PKG. In addition, pretreatment with tauroursodeoxycholic acid (TUDCA), a specific inhibitor of ER stress, could not further promote the VNP's cardioprotective effect in diabetic rats. In vitro H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation and incubated with or without VNP (10(-8) mol/l). Gene knockdown of PKG1 alpha with siRNA blunted VNP inhibition of ER stress and apoptosis, while overexpression of PKG1 alpha resulted in significant decreased ER stress and apoptosis. VNP protects the diabetic heart against ischemia-reperfusion injury by inhibiting ER stress via the cGMP-PKG signaling pathway. These results suggest that VNP may have potential therapeutic value for the diabetic patients with ischemic heart disease.