Amelioration of circadian disruption and calcium-handling protein defects by choline alleviates cardiac remodeling in abdominal aorta coarctation rats
Amelioration of circadian disruption and calcium-handling protein defects by choline alleviates cardiac remodeling in abdominal aorta coarctation rats
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胆碱改善昼夜节律紊乱和钙处理蛋白缺陷可减轻腹主动脉缩窄大鼠的心脏重塑
DOI：
10.1038/s41374-021-00578-6
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发表时间：
2021-03-01
影响因子：
5
通讯作者：
Zang, Wei-Jin
中科院分区：
文献类型：
--
作者：
He, Xi;Yang, Si;Zang, Wei-Jin
胆碱通过改善昼夜节律紊乱和减少钙处理蛋白缺陷减轻腹主动脉缩窄诱导的心脏重构和心功能不全。胆碱对迷走神经活动的调节可能对心脏重构和心力衰竭具有治疗潜力。导致心力衰竭的关键病理生理过程是心脏重构，这一术语指的是心脏肥大、纤维化和凋亡。我们探讨了心脏重构中的昼夜节律紊乱和钙稳态失调，并研究了胆碱的心脏保护作用。实验采用Sprague-Dawley大鼠腹主动脉缩窄（AAC）心脏重构模型。通过将新生大鼠心肌细胞暴露于血管紧张素II诱导体外心肌细胞重塑。在正常的24小时光/暗周期中，AAC大鼠心脏中哺乳动物时钟的7个主要组成部分（Bmal 1，Clock，Rev-erb alpha，Per 1/2和Cry 1/2）的转录水平的昼夜节律发生了改变。AAC还上调介导大鼠心脏中钙池操作的Ca 2+内流/受体操作的Ca 2+内流的蛋白质（基质相互作用分子1 [STIM 1]、Orai 1和瞬时受体电位规范6 [TRPC 6]）的水平。此外，胆碱改善了昼夜节律的破坏，减少了上调的蛋白质水平的STIM 1，Orai 1，和TRPC 6，并减轻心功能不全和重塑（证明由衰减的心脏肥大，纤维化和细胞凋亡）在AAC大鼠。体外分析表明，胆碱改善钙超载，下调STIM 1，Orai 1和TRPC 6，并抑制thapsiglavin诱导的钙池操作的钙离子内流和1-油酰-2-乙酰基-sn-甘油诱导的受体操作的钙离子内流在血管紧张素II处理的心肌细胞。总之，胆碱减弱AAC诱导的心脏重构和心功能不全，这与改善昼夜节律紊乱和减弱钙处理蛋白缺陷有关。胆碱调节迷走神经活动的昼夜节律和钙稳态可能对心脏重塑和心力衰竭具有治疗潜力。
Choline attenuates abdominal aortic coarctation-induced cardiac remodeling and cardiac dysfunction, by amelioration of circadian rhythm disruption and attenuation of calcium-handling protein defects. Modulation of vagal activity by choline may have therapeutic potential for cardiac remodeling and heart failure.The key pathophysiological process leading to heart failure is cardiac remodeling, a term referring to cardiac hypertrophy, fibrosis, and apoptosis. We explored circadian rhythm disruption and calcium dyshomeostasis in cardiac remodeling and investigated the cardioprotective effect of choline. The experiments were conducted using a model of cardiac remodeling by abdominal aorta coarctation (AAC) in Sprague-Dawley rats. In vitro cardiomyocyte remodeling was induced by exposing neonatal rat cardiomyocytes to angiotensin II. The circadian rhythms of the transcript levels of the seven major components of the mammalian clock (Bmal1, Clock, Rev-erb alpha, Per1/2, and Cry1/2) were altered in AAC rat hearts during a normal 24 h light/dark cycle. AAC also upregulated the levels of proteins that mediate store-operated Ca2+ entry/receptor-operated Ca2+ entry (stromal interaction molecule 1 [STIM1], Orai1, and transient receptor potential canonical 6 [TRPC6]) in rat hearts. Moreover, choline ameliorated circadian rhythm disruption, reduced the upregulated protein levels of STIM1, Orai1, and TRPC6, and alleviated cardiac dysfunction and remodeling (evidenced by attenuated cardiac hypertrophy, fibrosis, and apoptosis) in AAC rats. In vitro analyses showed that choline ameliorated calcium overload, downregulated STIM1, Orai1, and TRPC6, and inhibited thapsigargin-induced store-operated Ca2+ entry and 1-oleoyl-2-acetyl-sn-glycerol-induced receptor-operated Ca2+ entry in angiotensin II-treated cardiomyocytes. In conclusion, choline attenuated AAC-induced cardiac remodeling and cardiac dysfunction, which was related to amelioration of circadian rhythm disruption and attenuation of calcium-handling protein defects. Modulation of vagal activity by choline targeting the circadian rhythm and calcium homeostasis may have therapeutic potential for cardiac remodeling and heart failure.