Sun Ji-Min, Wang Chun-Miao, Guo Zeng, Hao Yu-Yu, Xie Yang-Jing, Gu Jian, Wang Ai-Ling
Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.
Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China.
Mol Med Rep. 2015 Mar;11(3):1845-50. doi: 10.3892/mmr.2014.2988. Epub 2014 Nov 20.
Cardiac hypertrophy is a compensatory mechanism that occurs in conjunction with cardiovascular diseases. Although hypertrophy of the myocardium provides certain benefits during the early stages of cardiovascular disease, prolonged hypertrophy is potentially harmful to the heart and can result in arrhythmia and heart failure. The aim of this study was to investigate whether an ATP‑sensitive K+ (KATP) channel agonist was capable of reducing isoproterenol (Iso)‑induced cardiac hypertrophy and modulating myocardial connexin43 (Cx43) expression. Fifty male Sprague Dawley rats were randomly assigned to five groups: Normal, vehicle, nicorandil, glibenclamide and nicorandil plus glibenclamide. Rats in the four treatment groups received Iso injection for seven days, followed by administration with saline, nicorandil, glibenclamide or a combination of nicorandil and glibenclamide, respectively, for four weeks. Cardiac hypertrophy was then evaluated by measuring body weight, heart weight and left‑ventricular weight, and plasma B‑type natriuretic peptide levels were evaluated by ELISA. Immunocytochemistry and a reverse transcription‑polymerase chain reaction were performed to detect the spatial distribution and gene expression of myocardial Cx43, respectively. The KATP channel agonist nicorandil markedly attenuated the degree of myocardial hypertrophy induced by Iso as compared with the vehicle group. Myocardial Cx43 expression was significantly decreased and redistributed following cardiac hypertrophy. The decrease and redistribution of Cx43 was reduced following treatment with the KATP channel agonist nicorandil. Addition of the KATP channel blocker glibenclamide eliminated the beneficial effects of nicorandil against hypertrophy and on connexin43. In conclusion, the present study indicated that chronic use of KATP channel agonists following cardiac hypertrophy can attenuate ventricular remodeling and upregulate the expression level and spatial distribution of Cx43.
心脏肥大是一种与心血管疾病相关的代偿机制。虽然心肌肥大在心血管疾病的早期阶段有一定益处，但长期肥大对心脏有潜在危害，可导致心律失常和心力衰竭。本研究的目的是探讨ATP敏感性钾离子（KATP）通道激动剂是否能够减轻异丙肾上腺素（Iso）诱导的心脏肥大，并调节心肌连接蛋白43（Cx43）的表达。将50只雄性Sprague Dawley大鼠随机分为五组：正常组、溶剂对照组、尼可地尔组、格列本脲组和尼可地尔加格列本脲组。四个治疗组的大鼠接受Iso注射7天，随后分别给予生理盐水、尼可地尔、格列本脲或尼可地尔与格列本脲的组合，持续4周。然后通过测量体重、心脏重量和左心室重量评估心脏肥大情况，并通过酶联免疫吸附测定法评估血浆B型利钠肽水平。分别进行免疫细胞化学和逆转录聚合酶链反应以检测心肌Cx43的空间分布和基因表达。与溶剂对照组相比，KATP通道激动剂尼可地尔显著减轻了Iso诱导的心肌肥大程度。心脏肥大后心肌Cx43表达显著降低并重新分布。用KATP通道激动剂尼可地尔治疗后，Cx43的降低和重新分布得到缓解。加入KATP通道阻滞剂格列本脲消除了尼可地尔对肥大和连接蛋白43的有益作用。总之，本研究表明心脏肥大后长期使用KATP通道激动剂可减轻心室重构，并上调Cx43的表达水平和空间分布。
