Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance
Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance
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Ghrelin 通过调节激活素 A-卵泡抑素失衡来抑制心肌梗死后心力衰竭大鼠的心脏纤维化。
DOI：
10.1016/j.peptides.2017.10.018
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发表时间：
2018-01-01
期刊：
影响因子：
3
通讯作者：
Yang, Ping
中科院分区：
文献类型：
--
作者：
Yang, Chunyan;Liu, Jinsha;Yang, Ping
Ghrelin是一种生长激素释放肽，有可能改善心脏功能，但其机制尚不清楚。本研究通过结扎冠状动脉左前降支(LAD)建立大鼠心力衰竭(HF)模型，皮下注射Ghrelin(100 mU g/kg，2次/d)，培养乳鼠心肌细胞，分别用Ang II(0.1 mU M)和Ghrelin(0.1 mU M)刺激心肌细胞，以探讨Ghrelin在心肌重塑中的作用机制。测定血流动力学变化和血清脑利钠肽(BNP)浓度，评价心功能。左心室重量指数(LVMI)、苏木精-伊红(H&E)染色和Masson‘s三色染色评价心肌纤维化程度。有趣的是，Ghrelin通过抑制纤维组织的增殖显著改善了心脏功能。为进一步探讨Ghrelin干预心肌纤维化的机制，采用免疫组织化学方法检测激活素A(Act A)及其阻断剂卵泡抑素(Folistatin，FS)在心肌梗死(MI)大鼠心肌组织中的表达，发现心肌梗死(MI)时Act A水平显著升高，Ghrelin治疗下调了Act A的表达。相比之下，FS在所有实验组中的表达没有明显变化。此外，Ghrelin可降低Ang II诱导的原代培养大鼠心肌细胞Act A的表达，而对FS的表达无影响(实时定量聚合酶链式反应和酶联免疫吸附试验)。因此，Ghrelin纠正了A/FS法案的不平衡。3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴化法显示，经ActA处理的原代培养的大鼠心脏成纤维细胞(CFs)增殖明显增加，I型和III型胶原(Col I和Col III)表达增强(实时定量PCR)。这些数据表明，Ghrelin通过调节A/FS失衡，抑制心肌纤维化，减轻左室重构，最终改善心功能。
Ghrelin, a growth hormone-releasing peptide, potentially improves cardiac function, but the mechanisms remain unclear. In the study, the rat heart failure (HF) model was established by ligating the left anterior descending coronary artery (LAD) and treated with ghrelin (100 mu g/kg, subcutaneous injection, bid); neonatal rat cardiomyocytes were cultured and stimulated with Ang II (0.1 mu M) and ghrelin(0.1 mu M) to explore the underlying mechanism of ghrelin in myocardial remodeling. Hemodynamic changes and serum brain natriuretic peptide (BNP) concentrations were measured to assess cardiac function. Left ventricular mass index (LVMI), hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were performed to evaluate myocardial fibrosis. Interestingly, ghrelin significantly improved cardiac function by inhibiting fibrous tissue proliferation. To further explore the mechanisms by which ghrelin interferes with myocardial fibrosis, the levels of activin A (Act A) and its blocker-follistatin (FS) were examined by immunohistochemistry; Act A levels were significantly increased in the myocardial infarction (MI), and ghrelin administeration downregulated Act A expression. In contrast, FS expression showed no significant change in all experimental groups. Furthermore, ghrelin decreased Ang II-induced Act A expression with no effect on FS expression in primary rat cardiomyocytes in vitro (real-time quantitative PCR and ELISA). Thus, ghrelin corrected the Act A/FS imbalance. Finally, Act A treated cultured primary rat cardiac fibroblasts (CFs) showed increased proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay] and enhanced expressions of type I and type III collagen (Col I and Col III) (real-time quantitative PCR). These data suggest that ghrelin inhibits myocardial fibrosis, attenuates left ventricular remodeling, and eventually improves cardiac function by adjusting Act A/FS imbalance.