Abstract
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-erbα, 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.