Lee Tsung-Ming, Chen Wei-Ting, Yang Chen-Chia, Lin Shinn-Zong, Chang Nen-Chung
Department of Medicine, Cardiology Section, China Medical University-An Nan Hospital, Tainan, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
J Cell Mol Med. 2015 Feb;19(2):418-29. doi: 10.1111/jcmm.12465. Epub 2014 Nov 11.
We investigated whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression in post-infarcted normoglycemic rats, focusing on adenosine and reactive oxygen species production. DPP-4 bound adenosine deaminase has been shown to catalyse extracellular adenosine to inosine. DPP-4 inhibitors increased adenosine levels by inhibiting the complex formation. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline or sitagliptin in in vivo and ex vivo studies. Post-infarction was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Compared with vehicle, infarcted rats treated with sitagliptin significantly increased interstitial adenosine levels and attenuated oxidative stress. Sympathetic hyperinnervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed a similar effect of erythro-9-(2-hydroxy-3-nonyl) adenine (an adenosine deaminase inhibitor) to sitagliptin on attenuated levels of superoxide and NGF. Furthermore, the beneficial effects of sitagliptin on superoxide anion production and NGF levels can be reversed by 8-cyclopentyl-1,3-dipropulxanthine (adenosine A1 receptor antagonist) and exogenous hypoxanthine. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation via adenosine A1 receptor and xanthine oxidase-dependent pathways, which converge through the attenuated formation of superoxide in the non-diabetic infarcted rats.
我们研究了二肽基肽酶-4（DPP-4）抑制剂西他列汀是否通过抑制梗死正常血糖大鼠的神经生长因子（NGF）表达来减轻心律失常，重点关注腺苷和活性氧的产生。已证明与腺苷脱氨酶结合的DPP-4可催化细胞外腺苷转化为肌苷。DPP-4抑制剂通过抑制复合物形成来增加腺苷水平。在体内和体外研究中，将正常血糖的雄性Wistar大鼠进行冠状动脉结扎，然后随机分为生理盐水组或西他列汀组。通过心肌超氧化物、硝基酪氨酸和二氢乙锭荧光染色测量，梗死与氧化应激增加有关。心肌去甲肾上腺素水平的测量显示，与假手术组相比，接受载体治疗的梗死大鼠有显著升高。与载体相比，用西他列汀治疗的梗死大鼠显著增加了间质腺苷水平并减轻了氧化应激。通过免疫荧光分析、蛋白质印迹以及NGF的实时定量逆转录聚合酶链反应评估，给予西他列汀后交感神经超支配减弱。西他列汀治疗的梗死大鼠的心律失常评分显著低于载体组。体外研究表明，红细胞-9-（2-羟基-3-壬基）腺嘌呤（一种腺苷脱氨酶抑制剂）对超氧化物和NGF水平的降低作用与西他列汀相似。此外，8-环戊基-1,3-二丙基黄嘌呤（腺苷A1受体拮抗剂）和外源性次黄嘌呤可逆转西他列汀对超氧阴离子产生和NGF水平的有益作用。西他列汀通过腺苷A1受体和黄嘌呤氧化酶依赖性途径减轻交感神经支配，从而保护心室心律失常，这两条途径在非糖尿病梗死大鼠中通过超氧化物形成的减弱而汇聚。
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