Stachydrine hydrochloride alleviates pressure overload-induced heart failure and calcium mishandling on mice
Stachydrine hydrochloride alleviates pressure overload-induced heart failure and calcium mishandling on mice
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DOI：
10.1016/j.jep.2019.112306
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发表时间：
2020-02-10
影响因子：
5.4
通讯作者：
Lu, Rong
中科院分区：
文献类型：
--
作者：
Chen, Hui-Hua;Wang, Si-Ning;Lu, Rong
民族药理学相关性：传统中药益母草。在治疗心血管疾病方面有着悠久的历史。盐酸水苏碱是从益母草中提取的主要活性成分，已被证明具有心脏保护作用。然而，迄今为止，盐酸水苏碱的潜在机制尚未得到全面的研究。本研究的目的：本研究的目的是调查盐酸水苏碱在心力衰竭中的保护作用，并阐明其可能的作用机制。材料和方法：在体内，对C57 BL/6 J小鼠进行横向主动脉收缩，此后，每日灌胃给予7.2 mg/kg替米沙坦（选择性AT 1 R拮抗剂作为阳性对照）和12 mg/kg盐酸水苏碱，持续4周。通过评估形态学变化以及超声心动图和血流动力学参数来评价心功能。在体外，用盐酸水苏碱处理新生大鼠心肌细胞或成年小鼠心肌细胞，并用苯肾上腺素（α-AR激动剂）激发。采用Langendorff错流灌流系统分离C57 BL/6 J小鼠心室肌细胞。用离子成像系统测定细胞内钙离子浓度。结果：盐酸水苏碱能改善TAC小鼠心肌细胞的心功能，提高钙瞬变幅度，抑制SR漏出和火花数。盐酸水苏碱可改善苯肾上腺素引起的肌节收缩、钙瞬变和钙火花增强。结论：盐酸水苏碱对心衰有一定的治疗作用。这些心脏保护作用可能与盐酸水苏碱通过抑制CaMKII的过度磷酸化来调节钙处理有关。
Ethnopharmacological relevance: Traditional Chinese medicine Leonurus japonicus Houtt. has a long history in the treatment of cardiovascular diseases. Stachydrine hydrochloride, the main bioactive ingredient extracted from Leonurus japonicus Houtt., has been shown to have cardioprotective effects. However, the underlying mechanisms of stachydrine hydrochloride haven't been comprehensively studied so far.Aim of the study: The aim of this study was to investigate the protective role of stachydrine hydrochloride in heart failure and elucidate its possible mechanisms of action.Materials and methods: In vivo, transverse aorta constriction was carried out in C57BL/6J mice, and thereafter, 7.2 mg/kg telmisartan (a selective AT1R antagonist as positive control) and 12 mg/kg stachydrine hydrochloride was administered daily intragastrically for 4 weeks. Cardiac function was evaluated by assessing morphological changes as well as echocardiographic and haemodynamic parameters. In vitro, neonatal rat cardiomyocytes or adult mice cardiomyocytes were treated with stachydrine hydrochloride and challenged with phenylephrine (alpha-AR agonist). Ventricular myocytes were isolated from the hearts of C57BL/6J mice by Langendorff crossflow perfusion system. Intracellular calcium was measured by an ion imaging system. The length and movement of sarcomere were traced to evaluate the systolic and diastolic function of single myocardial cells.Results: Stachydrine hydrochloride improved the cardiac function and calcium transient amplitudes, and inhibited the SR leakage and the amount of sparks in cardiac myocytes isolated from TAC mice. We also demonstrated that stachydrine hydrochloride could ameliorated phenylephrine-induced enhance in sarcomere contraction, calcium transients and calcium sparks. Moreover, our data shown that stachydrine hydrochloride blocked the hyper-phosphorylation of CaMKII, RyR2, PLN, and prevented the disassociation of FKBP12.6 from RyR2.Conclusion: Our results suggest that stachydrine hydrochloride exerts beneficial therapeutic effects against heart failure. These cardioprotective effects may be associated with the regulation of calcium handling by stachydrine hydrochloride through inhibiting the hyper-phosphorylation of CaMKII.