PCSK9 regulates myofibroblast transformation through the JAK2/STAT3 pathway to regulate fibrosis after myocardial infarction
PCSK9 regulates myofibroblast transformation through the JAK2/STAT3 pathway to regulate fibrosis after myocardial infarction
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DOI：
10.1016/j.bcp.2023.115996
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发表时间：
2024-01-09
影响因子：
5.8
通讯作者：
Li，Wei
中科院分区：
文献类型：
--
作者：
Bao，Hailong;Wang，Xu;Li，Wei
心脏纤维化在许多心血管疾病的发展中起着关键作用。这种现象的特点是肌成纤维细胞分泌的ECM蛋白过度沉积，导致心肌僵硬增加。枯草杆菌前蛋白转换酶9(PCSK9)是一种丝氨酸蛋白酶，属于原蛋白转换酶家族。它已成为降低血浆低密度脂蛋白胆固醇的可行治疗靶点。然而，PCSK9影响心脏纤维化的确切机制尚不清楚。在本研究中，在心肌梗死患者和心肌梗死大鼠模型中观察到循环中PCSK9蛋白水平的增加。此外，抑制大鼠循环中的PCSK9被发现可以减少梗死后的纤维化。体外实验进一步证明PCSK9的过表达或细胞外PCSK9重组蛋白的刺激可促进心脏成纤维细胞向肌成纤维细胞的转化。这一过程也提高了胶原Ⅰ和Ⅲ以及α-SMA的蛋白水平。然而，当与STAT3抑制剂S3I-201共同孵育时，这些作用被抵消。这项研究表明，PCSK9可能主要通过JAK2/STAT3途径发挥心肌纤维化的新调节作用。
Cardiac fibrosis is pivotal in the progression of numerous cardiovascular diseases. This phenomenon is hallmarked by an excessive deposition of ECM protein secreted by myofibroblasts, leading to increased myocardial stiffness. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that belongs to the proprotein-converting enzyme family. It has emerged as a viable therapeutic target for reducing plasma low-density lipoprotein cholesterol. However, the exact mechanism via which PCSK9 impacts cardiac fibrosis remains unclear. In the present research, an increase in circulating PCSK9 protein levels was observed in individuals with myocardial infarction and rat models of myocardial infarction. Moreover, the inhibition of circulating PCSK9 in rats was found to reduce post-infarction fibrosis. In vitro experiments further demonstrated that overexpression of PCSK9 or stimulation by extracellular PCSK9 recombinant protein enhanced the transformation of cardiac fibroblasts to myofibroblasts. This process also elevated collagen Ⅰ, and Ⅲ, as well as α-SMA protein levels. However, these effects were countered when co-incubated with the STAT3 inhibitor S3I-201. This study suggests that PCSK9 may function as a novel regulator of myocardial fibrosis, primarily via the JAK2/STAT3 pathway.