Stachytine Hydrochloride Improves Cardiac Function in Mice with ISO-Induced Heart Failure by Inhibiting the α-1,6-Fucosylation on N-Glycosylation of β1AR.
Stachytine Hydrochloride Improves Cardiac Function in Mice with ISO-Induced Heart Failure by Inhibiting the α-1,6-Fucosylation on N-Glycosylation of β1AR.
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盐酸水苏碱通过抑制 β1AR N-糖基化上的 α-1,6-岩藻糖基化改善 ISO 诱发心力衰竭小鼠的心脏功能
DOI：
10.3389/fphar.2021.834192
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发表时间：
2021
影响因子：
5.6
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Hu P;Guo S;Yang S;Wang S;Wang S;Shan X;Zhao P;Guo W;Xu M;Zhang C;Lu R;Chen H
研究背景：心血管疾病已成为严重威胁人类健康的重大公共卫生问题。各种心血管事件的累积效应最终会发展为慢性心功能不全甚至心力衰竭，而β1肾上腺素受体信号通路在这一过程中发挥着重要作用。盐酸水苏碱是益母草的主要活性成分，益母草是一种用于治疗妇科疾病的中药。现代研究发现盐酸水苏碱具有良好的心脏保护作用，但盐酸水苏碱是否对β1肾上腺素受体信号通路有影响尚不清楚。本研究旨在探讨盐酸水苏碱对β1肾上腺素受体信号通路的影响。 方法：本研究通过给小鼠连续输注异丙肾上腺素（40 mg/kg/天）和心室肌细胞，探讨了盐酸水苏碱（12 mg/kg/天）对心脏 β1 肾上腺素能受体信号通路的潜在机制。通过超声心动图、心脏血流动力学和组织学方法评估心脏形态和功能的变化，并通过蛋白质印迹和免疫荧光检测分子变化。在不同时间点用或不用异丙肾上腺素 (0.1 μMol)、PNGase F (10–2 单位/ml) 和盐酸水苏碱 (10 μMol) 治疗原代培养的成年小鼠或新生大鼠心室肌细胞。检测 N-糖基化、钙瞬变、收缩和松弛功能及相关信号的 α-1,6-岩藻糖基化。 结果：盐酸水苏碱可减少体内慢性 β1 肾上腺素能受体激活过程中的心脏重塑并调节血流动力学参数。连续异丙肾上腺素刺激后β1肾上腺素能受体的N-糖基化降低，而盐酸水苏碱可以增加异丙肾上腺素诱发心力衰竭小鼠心脏中β1AR的N-糖基化。 β1肾上腺素能受体N-糖基化减少会下调cAMP/PKA信号通路，抑制心肌兴奋和收缩耦合。盐酸水苏碱显着降低异丙肾上腺素诱导的具有 α-1,6-岩藻糖基化的心脏 N 连接糖蛋白。 结论：我们的研究结果表明，盐酸水苏碱通过减少α-1,6-岩藻糖基转移酶（FUT8）和α-1,3-甘露糖基糖蛋白4-β-N-乙酰氨基葡萄糖转移酶A（MGAT4a）来抑制N末端糖链上α-1,6-岩藻糖基化的合成，上调β1肾上腺素能受体上的N-糖基化水平，并维持cAMP/PKA 信号通路激活。
Background: Cardiovascular diseases have become a major public health problem that seriously threatens human health. The cumulative effects of various cardiovascular events will eventually develop into chronic heart insufficiency and even heart failure, and the β1 adrenergic receptor signal pathway plays an important role in this process. Stachytine hydrochloride is the main active ingredient of Yimucao, which is a traditional Chinese medicine used to treat gynecological diseases. Modern studies have found that stachytine hydrochloride has a good cardioprotective effect, but it is still unclear whether stachytine hydrochloride has an effect on the β1 adrenergic receptor signal pathway. The purpose of this study is to explore the effect of stachytine hydrochloride on the β1 adrenergic receptor signal pathway. Method: In this study, a continuous infusion of isoproterenol (40 mg/kg/day) was administered to mice and ventricular myocytes explored the potential mechanism of stachytine hydrochloride (12 mg/kg/day) on the β1 adrenergic receptor signal pathway in the heart. Evaluate changes in cardiac morphology and function by echocardiography, cardiac hemodynamics, and histological methods, and detect molecular changes by Western blot and immunofluorescence. Treat primary cultured adult mouse or neonatal rat ventricular myocytes with or without isoproterenol (0.1 μMol), PNGase F (10–2 units/ml), and stachytine hydrochloride (10 μMol) at different time points. Detect α-1,6-fucosylation on N-glycosylation, calcium transient, contraction, and relaxation function and related signals. Results: Stachytine hydrochloride reduces cardiac remodeling and modulates hemodynamic parameters during chronic β1 adrenergic receptor activation in vivo. The N-glycosylation of β1 adrenergic receptors decreased after continuous isoproterenol stimulation, while stachytine hydrochloride can increase the N-glycosylation of β1AR in the heart of mice with isoproterenol-induced heart failure. Decreased N-glycosylation of β1 adrenergic receptors will downregulate the cAMP/PKA signal pathway and inhibit myocardial excitation and contraction coupling. Stachytine hydrochloride significantly reduced isoproterenol-induced cardiac N-linked glycoproteins with α-1,6-fucosylation. Conclusion: Our results show that stachytine hydrochloride inhibits the synthesis of α-1,6-fucosylation on the N-terminal sugar chain by reducing α-1,6-fucosyltransferase (FUT8) and α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase A (MGAT4a), upregulating the N-glycosylation level on β1 adrenergic receptors, and maintaining cAMP/PKA signal pathway activation.
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