LIM kinase 2 activates cardiac fibroblasts and exacerbates postinfarction left ventricular remodeling via crosstalk between the canonical and non-canonical Wnt pathways.

Autor: Gong C; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China; Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215002, China., Chang L; Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210008, China; Department of Cardiology, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou 215000, China., Huang R; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China., Sun X; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China., Liu Y; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China., Wu S; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China., Wang L; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China., Xu B; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China; Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210008, China. Electronic address: xubiao62@nju.edu.cn., Wang L; Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, the Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, China; Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu 210008, China. Electronic address: wanglian@njglyy.com.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2024 Oct; Vol. 208, pp. 107347. Date of Electronic Publication: 2024 Aug 15.
DOI: 10.1016/j.phrs.2024.107347
Abstrakt: Ischemic heart failure rates rise despite decreased acute myocardial infarction (MI) mortality. Excessive myofibroblast activation post-MI leads to adverse remodeling. LIM kinases (LIMK1 and LIMK2) regulate cytoskeleton homeostasis and are pro-fibrotic markers in atrial fibrillation. However, their roles and mechanisms in postinfarction fibrosis and ventricular remodeling remain unclear. This study found that the expression of LIMKs elevated in the border zone (BZ) in mice MI models. LIMK1/2 double knockout (DKO) restrained pathological remodeling and reduced mortality by suppressing myofibroblast activation. By using adeno-associated virus (AAV) with a periostin promoter to overexpress LIMK1 or LIMK2, this study found that myofibroblast-specific LIMK2 overexpression diminished these effects in DKO mice, while LIMK1 did not. LIMK2 kinase activity was critical for myofibroblast proliferation by using AAV overexpressing mutant LIMK2 lack of kinase activity. According to phosphoproteome analysis, functional rescue experiments, co-immunoprecipitation, and protein-protein docking, LIMK2 led to the phosphorylation of β-catenin at Ser 552. LIMK2 nuclear translocation also played a role in myofibroblast proliferation after MI with the help of AAV overexpressing mutant LIMK2 without nuclear location signal. Chromatin immunoprecipitation sequencing identified that LIMK2 bound to Lrp6 promoter region in TGF-β treated cardiac fibroblasts, positively regulating Wnt signaling via Wnt receptor internalization. This study demonstrated that LIMK2 promoted myofibroblast proliferation and adverse cardiac remodeling after MI, by enhancing phospho-β-catenin (Ser552) and Lrp6 signaling. This suggested that LIMK2 could be a target for the treatment of postinfarction injury.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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