Institute of Biophysics, Czech Academy of Sciences, Brno, Czech Republic.
Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
J Pineal Res. 2016 Nov;61(4):493-503. doi: 10.1111/jpi.12366. Epub 2016 Oct 16.
Melatonin, a molecule involved in the regulation of circadian rhythms, has protective effects against myocardial injuries. However, its capability to regulate the maturation of cardiac progenitor cells is unclear. Recently, several studies have shown that melatonin inhibits the stabilization of hypoxia-inducible factors (HIFs), important signaling molecules with cardioprotective effects. In this study, by employing differentiating mouse embryonic stem cells, we report that melatonin significantly upregulated the expression of cardiac cell-specific markers (myosin heavy chains six and seven) as well as the percentage of myosin heavy chain-positive cells. Importantly, melatonin decreased HIF-1α stabilization and transcriptional activity and, in contrast, induced HIF-2α stabilization. Interestingly, the deletion of HIF-1α completely inhibited the pro-cardiomyogenic effect of melatonin as well as the melatonin-mediated HIF-2α stabilization. Moreover, melatonin increased Sirt-1 levels in a HIF-1α-dependent manner. Taken together, we provide new evidence of a time-specific inhibition of HIF-1α stabilization as an essential feature of melatonin-induced cardiomyogenesis and unexpected different roles of HIF-1α stabilization during various stages of cardiac development. These results uncover new mechanisms underlying the maturation of cardiac progenitor cells and can help in the development of novel strategies for using melatonin in cardiac regeneration therapy.
褪黑素是一种参与调节昼夜节律的分子，对心肌损伤具有保护作用。然而，其调节心脏祖细胞成熟的能力尚不清楚。最近的几项研究表明，褪黑素抑制了缺氧诱导因子（HIFs）的稳定，HIFs 是具有心脏保护作用的重要信号分子。在这项研究中，我们通过使用分化的小鼠胚胎干细胞报告称，褪黑素可显著上调心脏细胞特异性标志物（肌球蛋白重链六和七）的表达以及肌球蛋白重链阳性细胞的比例。重要的是，褪黑素降低了 HIF-1α的稳定和转录活性，相反，诱导了 HIF-2α的稳定。有趣的是，HIF-1α 的缺失完全抑制了褪黑素的促心肌生成作用以及褪黑素介导的 HIF-2α 稳定。此外，褪黑素以 HIF-1α 依赖的方式增加了 Sirt-1 水平。总之，我们提供了褪黑素诱导心肌发生过程中 HIF-1α 稳定的时间特异性抑制作为一个基本特征的新证据，以及在心脏发育的不同阶段 HIF-1α 稳定的意想不到的不同作用。这些结果揭示了心脏祖细胞成熟的新机制，并有助于开发使用褪黑素进行心脏再生治疗的新策略。
