Depressed calcium-handling proteins due to endoplasmic reticulum stress and apoptosis in the diabetic heart are attenuated by argirein
Depressed calcium-handling proteins due to endoplasmic reticulum stress and apoptosis in the diabetic heart are attenuated by argirein
复制标题
糖尿病心脏内质网应激和细胞凋亡引起的钙处理蛋白抑制可被阿甘油减弱
DOI：
10.1007/s00210-013-0852-5
复制
发表时间：
2013-06-01
影响因子：
3.6
通讯作者：
Dai, Y.
中科院分区：
文献类型：
--
作者：
Shi, F. H.;Cheng, Y. S.;Dai, Y.
糖尿病心肌病(DC)是糖尿病常见的一种特殊疾病，表现为内质网(ER)应激和钙调节蛋白的抑制。我们假设FKBP12.6、SERCA2a和CASQ2的异常是内质网应激和细胞凋亡的结果，这可能是由于炎症实体所致。这些异常可能归因于激活的NADPH氧化酶通过其抗炎活性对精氨酸酶(AR)做出反应的活性氧物种的产生。将SD大鼠随机分为6组。除正常组外，其余大鼠均注射链脲佐菌素(STZ；60 mg/kg，i.p)。一次。在注射STZ后的5至8周内，对大鼠进行治疗(以每天每公斤毫克计算，I.G.)使用氨基胍(AMG，100；一种诱导型一氧化氮合酶和AGEs抑制剂)或三种剂量的AR(50、100和200)。在体内和体外监测FKBP12.6、SERCA2a、CASQ2和内质网应激伴侣蛋白Bip和PERK以及细胞凋亡分子。体内DC的心脏功能受损，FKBP12.6、SERCA2a和CASQ2表达下调，体外高糖孵育的心肌细胞中也发现异常的钙处理蛋白。在体内和体外，表现为Bip和PERK上调的内质网应激主要与DNA梯状条带相关，上调Bax和下调bcl2。与AMG相比，AR能有效地减轻这些异常。糖尿病心肌有炎症实体，表现为内质网应激，导致钙调节蛋白表达下调。AR有可能通过减轻心肌中受抑制的钙处理蛋白、激活的内质网应激和细胞凋亡来管理DC。
Diabetic cardiomyopathy (DC) is a unique disease frequently complicated to diabetes mellitus, manifesting endoplasmic reticulum (ER) stress and depressed calcium-handling proteins. We hypothesized that the abnormal FKBP12.6, SERCA2a, and CASQ2 are consequent to ER stress and apoptosis that are likely due to an entity of inflammation. These abnormalities may be attributed to reactive oxygen species genesis from activated NADPH oxidase which could respond to argirein (AR) through its anti-inflammatory activity. Sprague Dawley rats were randomly divided into six groups. Except the normal group, rats were injected with streptozotocin (STZ; 60 mg/kg, i.p.) once. During weeks 5 to 8 following STZ injection, rats were treated (in milligrams per kilogram per day, i.g.) with aminoguanidine (AMG, 100; an inducible nitric oxide synthase and AGEs inhibitor) or three doses of AR (50, 100, and 200). FKBP12.6, SERCA2a, and CASQ2 and ER stress chaperones Bip and PERK and apoptotic molecules were monitored in vivo and in vitro. Impaired cardiac performance and downregulated FKBP12.6, SERCA2a, and CASQ2 were significant in DC in vivo, and abnormal calcium-handling proteins were also found in high-glucose-incubated myocytes in vitro. ER stress manifested by upregulated Bip and PERK was predominant in association with DNA ladder and upregulated Bax and downregulated BCL-2 in vivo and in vitro. AR is effective to attenuate these abnormalities compared to AMG. Diabetic myocardium has inflammatory entity expressed as ER stress contributing to downregulated calcium-handling proteins. AR has potential in managing DC through attenuating depressed calcium-handling proteins, activated ER stress, and apoptosis in the myocardium.