Higenamine Attenuates Cardiac Fibroblast Activation and Fibrosis via Inhibition of TGF-β1/Smad Signaling.
Higenamine Attenuates Cardiac Fibroblast Activation and Fibrosis via Inhibition of TGF-β1/Smad Signaling.
复制标题
DOI：
10.1016/j.ejphar.2021.174013
复制
发表时间：
2021-03
影响因子：
5
通讯作者：
Jingbo Zhu;W. Ling;Chao Xue;ZhenYu Zhou;Yishuai Zhang;C. Yan;Mei-ping Wu
中科院分区：
文献类型：
--
作者：
Jingbo Zhu;W. Ling;Chao Xue;ZhenYu Zhou;Yishuai Zhang;C. Yan;Mei-ping Wu
高铁胺（HG）是许多广泛使用的中草药的主要活性成分之一，也是欧洲和北美保健品的常见成分。一些研究小组，包括我们自己的研究小组，先前已经证明了HG对急性缺血性损伤期间心肌细胞死亡的有益作用。然而，HG对慢性心脏重塑（如心脏纤维化）的影响尚不清楚。目的探讨HG在体内心肌纤维化中的作用及其细胞和分子机制。方法和结果慢性压力过载合并横断主动脉缩窄（TAC）显著增加小鼠心肌肥厚、纤维化和心功能障碍，而HG显著减轻了这些症状。同样，慢性输注异丙肾上腺素（ISO）诱导的心脏纤维化也显著减轻了HG。有趣的是，我们的研究结果显示HG对体外成年小鼠CM肥厚没有影响。然而，HG在体外抑制心脏成纤维细胞（CFs）的激活。此外，HG显著抑制TGF-β1诱导的成纤维细胞活化标志物ACTA2的表达，同时，HG抑制TGF-β1诱导的CFs中Smad2/3的磷酸化。HG还降低了I型胶原和III型胶原等细胞外基质分子的表达。令我们惊讶的是，HG对CFs激活的抑制作用独立于β2肾上腺素能受体（β2-AR）的激活，而β2-AR介导了HG拮抗CMs凋亡的作用。结论HG至少部分通过抑制TGF-β1/Smad信号和CFs激活来改善病理性心肌纤维化和功能障碍。
RationaleHigenamine (HG), is one of the main active components in many widely used Chinese herbs, and a common ingredient of health products in Europe and North America. Several groups, including our own, have previously shown the beneficial effects of HG against cardiomyocyte death during acute ischemic damage. However, the effect of HG on chronic cardiac remodeling, such as cardiac fibrosis, remains unknown.ObjectiveHerein, we aim to investigate the role of HG in cardiac fibrosisin vivoas well as its cellular and molecular mechanisms.Methods and resultsChronic pressure overload with transverse aortic constriction (TAC) significantly increased cardiac hypertrophy, fibrosis, and cardiac dysfunction in mice, which were significantly attenuated by HG. Consistently, cardiac fibrosis induced by the chronic infusion of isoproterenol (ISO), was also significantly reduced by HG. Interestingly, our results showed that HG had no effect on adult mouse CM hypertrophyin vitro. However, HG suppressed the activation of cardiac fibroblasts (CFs)in vitro. Furthermore, TGF-β1-induced expression of ACTA2, a marker of fibroblast activation, was significantly suppressed by HG. Concomitantly, HG inhibited TGF-β1-induced phosphorylation of Smad2/3 in CFs. HG also reduced the expression of extracellular matrix molecules such as collagen I and collagen III. To our surprise, the inhibitory effect of HG on CFs activation was independent of the activation of the beta2 adrenergic receptor (β2-AR) that is known to mediate the effect of HG on antagonizing CMs apoptosis.ConclusionOur findings suggest that HG ameliorates pathological cardiac fibrosis and dysfunction at least partially by suppressing TGF-β1/Smad signaling and CFs activation.