Department of Obstetrics and Gynecology, High-Tech Hospital, The First Affiliated Hospital, Nanchang University, Nanchang, China.
Department of Cardiology, the Second Medical Center, Chinese PLA General Hospital, National Clinical Research Center for Geriatric Diseases, Beijing, China.
J Cell Mol Med. 2020 Jul;24(14):7907-7914. doi: 10.1111/jcmm.15423. Epub 2020 Jun 11.
Increased expression and activity of cardiac and circulating cathepsin D and soluble fms-like tyrosine kinase-1 (sFlt-1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23-kD prolactin (PRL) to 16-kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY-411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt-1, reduced Hes1, phosphorylated Stat3 (p-Stat3), VEGFA and PDGFB, and promoted cleavage of 23k-D PRL to 16-kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt-1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.
已证实，心脏和循环组织中组织蛋白酶 D 和可溶性 fms 样酪氨酸激酶-1（sFlt-1）的表达和活性增加，可分别通过促进 23kD 泌乳素（PRL）裂解为 16kD PRL 和中和血管内皮生长因子（VEGF），从而诱导和促进围产期心肌病（PPCM）。我们假设 Hes1 的激活通过激活 Stat3 来抑制组织蛋白酶 D，从而减轻 PPCM 的发展。在本研究中，我们旨在研究 Notch1/Hes1 通路在 PPCM 中的作用。在产前 3 天至产后 3 周期间，给怀孕的小鼠喂食 LY-411575（Notch 抑制剂，10mg/kg/d）。通过超声心动图和组织学分析评估心室功能和病理学。通过 Western blot 分析检测蛋白水平的表达。结果发现，Notch1 的抑制显著促进了产后心室扩张、心肌肥大和心肌间质纤维化，并抑制了心肌血管生成。Western blot 分析显示，Notch1 的抑制显著增加了组织蛋白酶 D 和 sFlt-1，降低了 Hes1、磷酸化 Stat3（p-Stat3）、VEGFA 和 PDGFB，并促进了 23kD PRL 裂解为 16kD PRL。总之，Notch1/Hes1 通路的抑制通过增加组织蛋白酶 D 和 sFlt-1 的表达，诱导并促进 PPCM。Notch1/Hes1 是预防和治疗 PPCM 的有前途的靶点。
