Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload
Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload
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心肌细胞中混合谱系激酶 3 (MLK3) 信号传导诱导的焦亡和铁死亡对于压力超负荷引起的心肌纤维化至关重要
DOI：
10.1038/s41419-020-02777-3
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发表时间：
2020-07-24
影响因子：
9
通讯作者：
Wang, Lingjun
中科院分区：
文献类型：
--
作者：
Wang, Junyan;Deng, Bo;Wang, Lingjun
慢性心力衰竭（CHF）是许多心血管疾病的最终结果，也是老年人口面临的严重健康问题。混合谱系激酶 3 (MLK3) 是 MAP3K 家族的成员，与衰老、炎症、氧化应激和相关疾病（例如 CHF）相关。据报道，MLK3 在防止心肌细胞损伤方面发挥着重要作用；然而，其在心肌纤维化中的作用尚不清楚。为了研究 MLK3 在心肌纤维化中的作用，我们抑制 MLK3 的表达，并检查 TAC 小鼠的心脏功能和重构。此外，我们评估了心室细胞中 MLK3 蛋白及其下游相关蛋白的表达。我们发现MLK3主要调节NF-κB/NLRP3信号通路介导的炎症，并且焦亡在CHF早期导致心肌纤维化。同样，MLK3主要调节JNK/p53信号通路介导的氧化应激，铁死亡导致CHF晚期心肌纤维化。我们还发现，促进miR-351的表达可以抑制MLK3的表达，并显着改善TAC小鼠的心功能。这些结果表明，心肌细胞中 MLK3 信号传导诱导的细胞焦亡和铁死亡对于压力超负荷时出现的不良心肌纤维化至关重要。此外，miR-351对压力超负荷引起的心力衰竭心室重构具有保护作用，可能是MLK3调节的关键靶点。
Chronic heart failure (CHF) is the final outcome of many cardiovascular diseases, and is a severe health issue faced by the elderly population. Mixed lineage kinase 3 (MLK3), a member of MAP3K family, is associated with aging, inflammation, oxidative stress, and related diseases, such as CHF. MLK3 has also been reported to play an important role in protecting against cardiomyocyte injury; however, its function in myocardial fibrosis is unknown. To investigate the role of MLK3 in myocardial fibrosis, we inhibited the expression of MLK3, and examined cardiac function and remodeling in TAC mice. In addition, we assessed the expression of MLK3 protein in ventricular cells and its downstream associated protein. We found that MLK3 mainly regulates NF-κB/NLRP3 signaling pathway-mediated inflammation and that pyroptosis causes myocardial fibrosis in the early stages of CHF. Similarly, MLK3 mainly regulates the JNK/p53 signaling pathway-mediated oxidative stress and that ferroptosis causes myocardial fibrosis in the advanced stages of CHF. We also found that promoting the expression of miR-351 can inhibit the expression of MLK3, and significantly improve cardiac function in mice subjected to TAC. These results suggest the pyroptosis and ferroptosis induced by MLK3 signaling in cardiomyocytes are essential for adverse myocardial fibrosis, in response to pressure overload. Furthermore, miR-351, which has a protective effect on ventricular remodeling in heart failure caused by pressure overload, may be a key target for the regulation of MLK3.