2. Academic Validation
  3. PCSK9 Enhances Cardiac Fibrogenesis via the Activation of Toll-like Receptor and NLRP3 Inflammasome Signaling

PCSK9 Enhances Cardiac Fibrogenesis via the Activation of Toll-like Receptor and NLRP3 Inflammasome Signaling

  • Int J Mol Sci. 2025 Feb 23;26(5):1921. doi: 10.3390/ijms26051921.
Cheng-Chih Chung 1 2 3,  Yu-Hsun Kao 4 5,  Yao-Chang Chen 6,  Yung-Kuo Lin 1 2 3,  Satoshi Higa 7,  Kai-Cheng Hsu 8 9,  Yi-Jen Chen 1 2 3 4
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 2 Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
  • 3 Taipei Heart Institute, Taipei Medical University, Taipei 110, Taiwan.
  • 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
  • 5 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
  • 6 Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan.
  • 7 Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 1199, Japan.
  • 8 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
  • 9 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
PMID: 40076547 DOI: 10.3390/ijms26051921
Abstract

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.

Keywords

NLRP3; PCSK9; fibroblasts; fibrosis; inflammasome; toll-like receptor.

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