Liu Yu, Guo Yinfang, Huang Weilu, Deng Ke-Yu, Qian Yisong, Xin Hong-Bo
Cardiovascular Research Center, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Department of Medical Records, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Front Endocrinol (Lausanne). 2018 Dec 19;9:770. doi: 10.3389/fendo.2018.00770. eCollection 2018.
17β-Estradiol (E2) is the major estrogen secreted by the premenopausal ovary and shows dual effects on cell apoptosis under pathological conditions. E2 was previously shown to increase CD38 mRNA and protein expression in myometrial smooth muscle, but its function and mechanism remain largely unknown. Here we investigated the role of E2 in hypoxia-induced apoptosis in mouse airway smooth muscle cells (ASMCs) and explored the underlying mechanisms. Results showed that E2 significantly increased CD38 expression at both mRNA and protein levels, accompanied with decreased SIRT1 levels in ASMCs. By using primary ASMCs from the wild type (WT) and the smooth muscle-specific CD38 knockout (CD38 KO) mice, we found that the down-regulation of SIRT1 induced by E2 was abolished in CD38 KO AMSCs. E2 promoted the acetylation of p53 in WT cells, and this effect was also diminished in the absence of CD38. In addition, E2 further activated CD38/SIRT1/p53 signal pathway and promoted cell apoptosis during hypoxia. However, these effects were reversed in CD38 KO ASMCs and by the specific SIRT1 activator Resveratrol. We also found that E2 enhanced CD38 expression through estrogen receptor. The data suggested that CD38 is a direct target for E2 which promotes hypoxia-induced AMSC apoptosis through SIRT1/p53 signal pathway.
17β-雌二醇（E2）是绝经前卵巢分泌的主要雌激素，在病理条件下对细胞凋亡具有双重作用。先前研究表明，E2可增加子宫肌层平滑肌中CD38的mRNA和蛋白表达，但其功能和机制仍不清楚。在此，我们研究了E2在小鼠气道平滑肌细胞（ASMCs）缺氧诱导凋亡中的作用，并探讨了其潜在机制。结果显示，E2显著增加了ASMCs中CD38在mRNA和蛋白水平的表达，同时伴随着SIRT1水平的降低。通过使用野生型（WT）和平滑肌特异性CD38基因敲除（CD38 KO）小鼠的原代ASMCs，我们发现E2诱导的SIRT1下调在CD38 KO AMSCs中被消除。E2促进了WT细胞中p53的乙酰化，在缺乏CD38的情况下，这种作用也减弱。此外，E2进一步激活了CD38/SIRT1/p53信号通路，并在缺氧期间促进细胞凋亡。然而，这些作用在CD38 KO ASMCs中以及通过特异性SIRT1激活剂白藜芦醇得到逆转。我们还发现E2通过雌激素受体增强了CD38的表达。数据表明，CD38是E2的直接靶点，E2通过SIRT1/p53信号通路促进缺氧诱导的AMSC凋亡。
