激肽释放酶抑制物/丝氨酸蛋白酶抑制剂 3C 通过激活 Nr4a1 调节糖酵解抑制心肌梗死后的心脏纤维化。
Kallistatin/Serpina3c inhibits cardiac fibrosis after myocardial infarction by regulating glycolysis via Nr4a1 activation.
机构信息
Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China.
Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210009, China.
出版信息
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166441. doi: 10.1016/j.bbadis.2022.166441. Epub 2022 May 14.
BACKGROUND
Fibrotic remodeling is an essential aspect of heart failure. Human kallistatin (KS, mouse Serpina3c homologs) inhibits fibrosis after myocardial infarction (MI) but the specific underlying mechanism is unknown.
METHODS
A total of 40 heart failure patients (HFPs) were enrolled and their plasma KS was measured using ELISA. Serpina3c and C57BL/6 mice were used to construct the MI model. TGF-β1 or a hypoxic condition was established to interfere with the functioning of cardiac fibroblasts (CFs). RNA-seq was performed to assess the effect of Serpina3c on the transcriptome.
FINDINGS
The levels of KS were used as a predictor of readmission among the HFPs. Serpina3c expression decreased in MI hearts and CFs. Serpina3c led to the aggravation of MI fibrosis, and increased the proliferation of CFs. The overexpression of Serpina3c in CFs had the opposite effect. Glycolysis-related genes were significantly increased in Serpina3c group by RNA-seq. Enolase (ENO1), which is a key enzyme in glycolysis, increased most significantly. Inhibition of ENO1 could antagonize the promotion of Serpina3c on the proliferation of CFs. Co-IP was performed to verify the interaction between Serpina3c and Nr4a1. Serpina3c inhibited the acetylation of Nr4a1 and increased the degradation of Nr4a1. Activation of Nr4a1 could negatively regulate the expression of ENO1 and inhibited the proliferation of Serpina3c CFs in Serpina3c MI mice.
INTERPRETATION
Serpina3c inhibits the transcriptional activation of ENO1 by regulating the acetylation of Nr4a1, thereby reducing the fibrosis after MI by inhibiting glycolysis. Serpina3c is a potential target for prevention and treatment of heart failure after MI.
背景
纤维化重塑是心力衰竭的一个重要方面。人激肽释放酶抑制剂（KS，鼠 Serpina3c 同源物）可抑制心肌梗死（MI）后的纤维化，但具体的潜在机制尚不清楚。
方法
共纳入 40 例心力衰竭患者（HFPs），采用 ELISA 法检测其血浆 KS 水平。采用 Serpina3c 和 C57BL/6 小鼠构建 MI 模型。用 TGF-β1 或缺氧条件干预心肌成纤维细胞（CFs）的功能。进行 RNA-seq 以评估 Serpina3c 对转录组的影响。
结果
KS 水平可作为 HFPs 再入院的预测指标。MI 心脏和 CFs 中的 Serpina3c 表达减少。Serpina3c 导致 MI 纤维化加重，CFs 增殖增加。CFs 中 Serpina3c 的过表达则产生相反的效果。RNA-seq 显示，Serpina3c 组糖酵解相关基因显著增加，其中烯醇化酶（ENO1）增加最显著。抑制 ENO1 可拮抗 Serpina3c 对 CFs 增殖的促进作用。通过 Co-IP 验证了 Serpina3c 与 Nr4a1 之间的相互作用。Serpina3c 抑制 Nr4a1 的乙酰化，增加 Nr4a1 的降解。Nr4a1 的激活可负调控 ENO1 的表达，并抑制 Serpina3c MI 小鼠中 Serpina3c CFs 的增殖。
结论
Serpina3c 通过调节 Nr4a1 的乙酰化来抑制 ENO1 的转录激活，从而通过抑制糖酵解减少 MI 后的纤维化。Serpina3c 是 MI 后心力衰竭预防和治疗的潜在靶点。
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