Research Lab for Clinical & Translational Medicine, Medical school, University of South China, Hengyang 421001, China; Institute of Cardiovascular Research, Key Laboratory Atherosclerology of Hunan Province, University of South China, Hengyang 421001, China.
The Third Hospital of Changsha, Changsha 410000, China.
Peptides. 2019 Jan;111:118-126. doi: 10.1016/j.peptides.2018.09.001. Epub 2018 Sep 12.
Ghrelin, a peptide hormone produced in the gastrointestinal tract, has recently been found to be associated with the onset of myocardial fibrosis (MF). The exact mechanism, however, remains elusive. This study sought to identify the function and mechanism of ghrelin on MF after acute myocardial infarction (AMI). AMI was established in Spraque-Dawley rats by ligation of the left anterior descending (LAD). Ghrelin or saline was intraperitoneally injected two times per day for 8 weeks after ligation. The weight of heart (mg) and the weight ratio of heart to body (mg/g) as well as the fibrotic area were increased, while serum level of ghrelin was decreased after AMI. Ghrelin significantly ameliorated MF and decreased deposition of collagens in perivascular fibrosis area. In addition, ghrelin inhibited Endothelial-to-mesenchymal transition (EndMT), a crucial process for MF, in perivascular fibrosis area and TGF-β1-induced human coronary artery endothelial cells (HCAECs). Mechanistically, ghrelin persistently decreased the phosphorylation of Smad2/3 and enhanced the expression of Smad7 and p-AMPK in vivo and in vitro. After the abolition of Smad7, GHSR-1a and AMPK pathway, the effect of ghrelin on EndMT was significantly inhibited. In conclusion, these results presented a novel finding that ghrelin attenuated MF after AMI via regulation EndMT in a GHSR-1a/AMPK/Smad7- dependent manner.
胃饥饿素是一种在胃肠道中产生的肽类激素，最近发现它与心肌纤维化（MF）的发生有关。然而，其确切机制仍不清楚。本研究旨在确定胃饥饿素在急性心肌梗死（AMI）后对 MF 的作用和机制。通过结扎左前降支（LAD）在 Spraque-Dawley 大鼠中建立 AMI。结扎后每天两次腹腔内注射胃饥饿素或生理盐水，持续 8 周。AMI 后，心脏重量（mg）和心脏重量与体重的比值（mg/g）以及纤维化面积增加，而血清胃饥饿素水平降低。胃饥饿素显著改善 MF 并减少血管周围纤维化区域胶原的沉积。此外，胃饥饿素抑制了血管周围纤维化区域的内皮-间充质转化（EndMT），这是 MF 的一个关键过程，以及 TGF-β1 诱导的人冠状动脉内皮细胞（HCAECs）中的 EndMT。在机制上，胃饥饿素持续降低 Smad2/3 的磷酸化，并增强体内和体外 Smad7 和 p-AMPK 的表达。在废除 Smad7、GHSR-1a 和 AMPK 途径后，胃饥饿素对 EndMT 的作用明显受到抑制。总之，这些结果表明，胃饥饿素通过 GHSR-1a/AMPK/Smad7 依赖性调节 EndMT 来减轻 AMI 后的 MF。
