蒙药苏格木勒-3汤通过calumenin调控心肌肥厚钙稳态失衡/抑制ERS机制研究

Currently, cardiovascular disease has become a hazard to the health of our people, the number of deaths due to cardiovascular diseases was rapidly rising. In heart failure, myocardial infarction, hypertension and other cardiovascular diseases, cardiomyocyte hypertrophy is a common pathological process. Mongolian medicine sugemule-3 (SD-3) is effective in the treatment of cardiovascular disease. In our previous study, we found SD-3 could significantly improve the cardiomyocyte hypertrophy of H9c2 induced by isoproterenol (ISO), increase the capacity of anti-oxidant and inhibit apoptosis. SD-3 reduced the concentration of Ca2+ in cardiomyocyte hypertrophy of H9c2 induced by ISO. Animal experiments found that SD-3 relieved cardiomyocyte hypertrophy in rats induced by ISO. Further study found SD-3 down-regulated ER stress molecule chaperone GRP78, enhanced calumenin in hypertrophy rats induced by ISO. Based on the above research, we hypothesized that SD-3 regulated calcium homeostasis, inhibited ER stress by the expression of calumenin to improve cardiomyocyte hypertrophy. The hypertrophy model of cardiomyocytes will be established and intervened by SD-3. The current project is proposed to systematically study calumenin protein, calcium homeostasis and ERS. This project will provide experimental evidence of SD-3.

心血管疾病是威胁人类健康的头号杀手，心肌肥厚是多种心血管疾病共同的病理特征之一。蒙药苏格木勒-3汤（SD-3）是蒙药治疗心血管疾病之良方。前期研究发现，SD-3可明显改善异丙肾上腺素（ISO）诱导的H9c2心肌细胞肥厚现象，增加心肌细胞抗氧化能力，抑制凋亡，并可减少肥厚模型中Ca2+浓度；动物实验发现SD-3缓解ISO导致的大鼠心肌肥厚，下调GRP78及提高calumenin蛋白的表达。我们推测：SD-3可能通过介导calumenin蛋白表达，调控钙稳态失衡，抑制ERS进而改善心肌肥厚症状。基于上述结果，本课题拟从SD-3改善心肌肥厚现象入手，综合研究SD-3对calumenin蛋白、钙稳态及ERS的影响。为具有疗效的SD-3改善心肌肥厚症状提供实验依据。

心血管疾病是威胁人类健康的头号杀手，心肌肥厚是多种心血管疾病共同的病理特征之一。蒙药苏格木勒-3汤（SD-3）是蒙药治疗心血管疾病之良方。前期研究发现，SD-3可明显改善异丙肾上腺素（ISO）诱导的H9c2心肌细胞肥厚现象，增加心肌细胞抗氧化能力，抑制凋亡，并可减少肥厚模型中Ca2+浓度；动物实验发现SD-3缓解ISO导致的大鼠心肌肥厚，下调GRP78及提高calumenin蛋白的表达。我们推测：SD-3可能通过介导calumenin蛋白表达，调控钙稳态失衡，抑制ERS进而改善心肌肥厚症状。本课题拟从动物水平和细胞水平研究苏格木勒-3汤改善心肌肥厚的作用。通过本项目的研究，得到以下结论：1. 证明苏格木勒-3汤水提液改善大鼠H9c2细胞损伤及肥大现象，其作用是通过上调Calumenin的表达来调控氧化应激和内质网应激进而影响凋亡的发生。2. 苏格木勒-3汤改善大鼠心率失常及心肌细胞肥厚等现象，其作用是通过上调Calumenin的表达进一步影响L型钙离子电流通道（IL-Ca）及Na+/Ca+交换电流通道（INCX）及超速激活延迟整流钾电流通道(IKur)、瞬时外向钾电流通道（Ito）进一步调控内质网应激最终缓解大鼠心肌细胞凋亡。3. 苏格木勒-3汤通过调控线粒体融合/分裂相关蛋白、线粒体凋亡相关蛋白及增加线粒体质量，而改善心衰大鼠的心功能。4. 基于气相色谱和质谱技术的大鼠血清代谢组学研究，推测ISO导致大鼠心力衰竭的内源代谢物及蒙药苏格木勒-3可能的作用途径。发现苏格木勒-3汤调控抗凋亡小分子S1P蛋白的表达改善心肌肥厚。为蒙药苏格木勒-3汤的进一步开发与利用提供理论基础和数据支撑。