Liu Zhongwei, Zhang Yong, Pan Shuo, Qiu Chuan, Jia Hao, Wang Yuan, Zhu Haitao
Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, People's Republic of China.
Department of Global Biostatistics and Data Science, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, New Orleans, Louisiana.
Am J Physiol Endocrinol Metab. 2021 Mar 1;320(3):E539-E550. doi: 10.1152/ajpendo.00450.2020. Epub 2021 Jan 18.
Association between receptor for advanced glycation end products (RAGE) and postmyocardial infarction (MI) ventricular arrhythmias (VAs) in diabetes was investigated. Correlation between premature ventricular contractions (PVCs) and serum advanced glycation end products (AGEs) content was analyzed in a cohort consisting of 101 patients with ST-segment elevated MI (STEMI). MI diabetic rats were treated with anti-receptor for AGE (RAGE) antibody. Electrocardiography was used to record VAs. Myocytes were isolated from adjacent area around infracted region. Immunofluorescent stains were used to evaluate the association between FKBP12.6 (FK506-bindingprotein 12.6) and ryanodine receptor 2 (RyR2). Calcium sparks were evaluated by confocal microscope. Protein expression and phosphorylation were assessed by Western blotting. Calcineurin (CaN) enzymatic activity and RyR2 channel activity were also determined. In the cohort study, significantly increased amount of PVC was found in STEMI patients with diabetes ( < 0.05). Serum AGE concentration was significantly positively correlated with PVC amount in patients with STEMI (= 0.416, < 0.001). Multivariate analysis showed that serum AGE concentration was independently and positively related to frequent PVCs (adjusted hazard ratio, 1.86; 95% CI, 1.09-3.18, = 0.022). In the animal study, increased glucose-regulated protein 78 (GRP78) expression, protein kinase RNA-like ER kinase (PERK) phosphorylation, CaN enzymatic activity, FKBP12.6-RyR2 disassociation, RyR2 channel opening, and endoplasmic reticulum (ER) calcium releasing were found in diabetic MI animals, which were attenuated by anti-RAGE antibody treatment. This RAGE blocking also significantly lowered the VA amount in diabetic MI animals. Activation of RAGE-dependent ER stress-mediated PERK/CaN/RyR2 signaling participated in post-MI VAs in diabetes. In this study, we proposed a possible mechanism interpreting the clinical scenario that after myocardial infarction (MI) patients were more vulnerable to ventricular arrhythmias (VAs) when complicated with diabetes. A cohort study revealed that advanced glycation end products (AGEs) accumulated in patients with diabetes and closely associated post-MI VAs. In vivo and in vitro studies indicated that receptor for AGEs (RAGE)-dependent endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK) pathway triggered VAs, via ER calcium releasing, through calcineurin/RyR2 mechanism.
研究了晚期糖基化终末产物受体（RAGE）与糖尿病患者心肌梗死后（MI）室性心律失常（VAs）之间的关联。在一个由101例ST段抬高型心肌梗死（STEMI）患者组成的队列中，分析了室性早搏（PVCs）与血清晚期糖基化终末产物（AGEs）含量之间的相关性。对MI糖尿病大鼠用抗AGE受体（RAGE）抗体进行治疗。采用心电图记录室性心律失常。从梗死区域周围的相邻区域分离心肌细胞。使用免疫荧光染色评估FKBP12.6（FK506结合蛋白12.6）与兰尼碱受体2（RyR2）之间的关联。通过共聚焦显微镜评估钙火花。通过蛋白质印迹法评估蛋白质表达和磷酸化。还测定了钙调神经磷酸酶（CaN）的酶活性和RyR2通道活性。在队列研究中，发现糖尿病STEMI患者的PVC数量显著增加（<0.05）。STEMI患者血清AGE浓度与PVC数量显著正相关（=0.416，<0.001）。多变量分析显示，血清AGE浓度与频发PVC独立正相关（调整后的风险比为1.86；95%可信区间为1.09 - 3.18，=0.022）。在动物研究中，发现糖尿病MI动物中葡萄糖调节蛋白78（GRP78）表达增加、蛋白激酶RNA样内质网激酶（PERK）磷酸化、CaN酶活性、FKBP12.6 - RyR2解离、RyR2通道开放以及内质网（ER）钙释放增加，而抗RAGE抗体治疗可使其减弱。这种RAGE阻断也显著降低了糖尿病MI动物的室性心律失常数量。RAGE依赖性内质网应激介导的PERK/CaN/RyR2信号通路的激活参与了糖尿病患者心肌梗死后的室性心律失常。在本研究中，我们提出了一种可能的机制来解释心肌梗死（MI）患者合并糖尿病时更易发生室性心律失常（VAs）的临床情况。一项队列研究显示，糖尿病患者体内晚期糖基化终末产物（AGEs）蓄积，且与心肌梗死后室性心律失常密切相关。体内和体外研究表明，AGE受体（RAGE）依赖性内质网（ER）应激蛋白激酶RNA样内质网激酶（PERK）途径通过内质网钙释放，经由钙调神经磷酸酶/RyR2机制引发室性心律失常。
