Chung Cheng-Chih, Kao Yu-Hsun, Chen Yao-Chang, Lin Yung-Kuo, Higa Satoshi, Hsu Kai-Cheng, Chen Yi-Jen
Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
Int J Mol Sci. 2025 Feb 23;26(5):1921. doi: 10.3390/ijms26051921.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel target for reducing low-density lipoprotein cholesterol. PCSK9 activates the atherosclerosis process through pro-inflammation signaling. Furthermore, the serum level of PCSK9 is positively correlated with mortality in patients with heart failure (HF). Cardiac fibrosis plays a crucial role in the pathophysiology of HF. In this study, we intended to examine whether PCSK9 can increase fibroblast activities and explore what its underlying mechanisms are. Migration, proliferation analyses, and Western blotting were used on human cardiac fibroblasts with and without PCSK9. Alirocumab (a PCSK9 inhibitor, 10 mg/kg/week intra-peritoneally for 28 consecutive days) was treated in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. PCSK9 (50, 100 ng/mL) increased proliferation, myofibroblast differentiation capability, and collagen type I production. Compared with control cells, PCSK9 (100 ng/mL)-treated cardiac fibroblasts showed higher nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), interleukin (IL)-1, myofibroblast differentiation, and collagen production capabilities, which were attenuated by MCC950 (an NLRP3 inhibitor, 100 μmol/L). PCSK9 upregulated Myd88 and NF-κB signaling, which were reduced by TAK242 (a toll-like receptor (TLR) 4 inhibitor, 10 μmol/L). Moreover, alirocumab significantly improved left ventricular systolic function and attenuated fibrosis in HF rats. In conclusion, PCSK9 upregulates NLRP3 signaling and the profibrotic activities of cardiac fibroblasts through the activation of TLR4/Myd88/NF-κB signaling.
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）已成为降低低密度脂蛋白胆固醇的新靶点。PCSK9通过促炎信号激活动脉粥样硬化进程。此外，PCSK9的血清水平与心力衰竭（HF）患者的死亡率呈正相关。心脏纤维化在HF的病理生理学中起关键作用。在本研究中，我们旨在研究PCSK9是否能增加成纤维细胞活性，并探索其潜在机制。对有或无PCSK9的人心脏成纤维细胞进行迁移、增殖分析和蛋白质印迹法。在异丙肾上腺素（100 mg/kg，皮下注射）诱导的HF大鼠中给予阿利西尤单抗（一种PCSK9抑制剂，10 mg/kg/周腹腔注射，连续28天）。PCSK9（50、100 ng/mL）增加了增殖、肌成纤维细胞分化能力和I型胶原蛋白的产生。与对照细胞相比，PCSK9（100 ng/mL）处理的心脏成纤维细胞显示出更高的核苷酸结合结构域（NOD）样受体蛋白3（NLRP3）、白细胞介素（IL）-1、肌成纤维细胞分化和胶原蛋白产生能力，而MCC950（一种NLRP3抑制剂，100 μmol/L）可使其减弱。PCSK9上调了Myd88和NF-κB信号，而TAK242（一种Toll样受体（TLR）4抑制剂，10 μmol/L）可使其降低。此外，阿利西尤单抗显著改善了HF大鼠的左心室收缩功能并减轻了纤维化。总之，PCSK9通过激活TLR4/Myd88/NF-κB信号上调NLRP3信号和心脏成纤维细胞的促纤维化活性。
