2. Academic Validation
  3. Macrophage MKL1 contributes to cardiac fibrosis in a mouse model of myocardial infarction

Macrophage MKL1 contributes to cardiac fibrosis in a mouse model of myocardial infarction

  • Life Sci. 2024 Nov 1:356:123036. doi: 10.1016/j.lfs.2024.123036.
Ke Cao 1,  Yuwen Zhu 2,  Yameng Kuai 2,  Baoyu Chen 3,  Qianwen Zhao 4,  Wenkui Yu 5
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
  • 3 Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. Electronic address: baoyuchen0617@njglyy.com.
  • 4 Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: cola@njmu.edu.cn.
  • 5 Department of Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. Electronic address: yudrnj@nju.edu.cn.
PMID: 39222836 DOI: 10.1016/j.lfs.2024.123036
Abstract

Aims: Cardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis.

Materials and methods: Cardiac fibrosis is induced by myocardial infarction (MI). The MKL1f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1ΔN200-Rosa26 mice.

Key findings: MKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI.

Significance: Our data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

Keywords

Cardiac fibrosis; MKL1; Macrophage; Myocardial infarction.

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