GPR30/NETosis抑制老年女性心肌纤维化关键信号转导机制研究

绝经后老年女性心肌纤维导致心衰的发生率明显高于老年男性，提示雌激素及其受体可能在其中发挥关键调控作用。我们前期首先证实雌激素受体GPR30通过ERK通路抑制心肌纤维化减轻心衰，但具体上下游机制不清。NEJM最新报道：中性粒细胞NETosis是衰老状态心肌纤维化全新的核心调控分子，其作用可能与ERK密切相关。结合文献回顾：衰老心肌组织通过多种细胞间作用高表达MMP-9加重心肌纤维化，而MMP-9的表达依赖于ERK通路调控。因此针对老年绝经后女性心脏保护我们提出科学假说：激活GPR30经ERK/MMP-9/NETosis是抑制老年女性心衰后心肌纤维化形成的特殊机制。本项目将采用GPR30转基因动物，在分子、细胞与在体水平研究证实并阐明该科学假说，阐明GPR30通过NETosis参与抵抗心肌纤维化具体分子机制，为老年女性心肌纤维化所致心衰治疗和雌激素心脏保护研究提供全新干预靶点和重要理论依据。

The incidence of heart failure induced by myocardial fibrosis in aging postmenopausal women is significantly higher than that in aging men, suggesting that estrogen and its receptors may play an important role in the phenomenon. We innovatively reported that the estrogen receptor GPR30 ameliorated heart failure via inhibiting myocardial fibrosis in an ERK-dependent manner, but the underlying mechanisms remained to be elucidated. The latest study in NEJM demonstrated that NETosis was the key regulatory mechanism involved in myocardial fibrosis in aging condition, which was closely related to ERK signaling. Our literature review also showed that overexpression of MMP-9 in aging myocardial tissues through pleiotropic intercellular effects aggravated myocardial fibrosis, and the expression of MMP-9 depended on the regulation of ERK signaling. Therefore, we speculate that activation of GPR30 via ERK/MMP-9/NETosis is a novel mechanism for inhibiting myocardial fibrosis in aging female with heart failure. This project aims to prove the hypothesis in molecular, cellular and animal level by using GPR30 transgenic mice and clarify the underlying mechanisms of GPR30 and NETosis involved in the myocardial fibrosis. In this way, we may provide new interventional targets and theoretical basis for heart failure treatment and estrogen cardioprotection.