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

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2024-08-31 DOI:10.1016/j.lfs.2024.123036

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引用次数: 0

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 MKL1^f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1^ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1^Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1^{ΔN200-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, MKL1^Mϕ-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.

查看原文本刊更多论文

巨噬细胞 MKL1 在心肌梗死小鼠模型中促进了心脏纤维化。

目的：心脏纤维化的特点是胶原蛋白在心脏内异常沉积。巨噬细胞的极化或浸润是加速胶原沉积的主要原因。我们试图研究 MKL1 在心脏纤维化发展过程中参与巨噬细胞的作用：心肌梗死（MI）诱发心肌纤维化。将MKL1f/f小鼠与Lyz2-cre小鼠杂交，产生巨噬细胞条件性MKL1基因敲除小鼠（MKL1ΔMφ）。此外，通过将 Lyz2-cre 小鼠与 MKL1ΔN200-Rosa26 小鼠杂交，构建了巨噬细胞条件性 MKL1 过表达小鼠（MKL1Mϕ-OE）：主要发现：缺血性心肌病（ICM）患者和诱发心肌梗死的小鼠的巨噬细胞中 MKL1 的表达均明显增加。巨噬细胞中 MKL1 的缺失可改善心肌梗死诱导的心脏纤维化后的心脏功能。同样，与对照组小鼠相比，MKL1Mϕ-OE 小鼠在心肌梗死后表现出更严重的心脏纤维化和更差的心脏功能。此外，服用小分子 MKL1 抑制剂 CCG-1423 也能减少心肌梗死后的胶原沉积：我们的数据证明了巨噬细胞中的MKL1有助于心脏纤维化的发病机制，并强化了靶向MKL1可能产生有效的心脏抗纤维化疗法的观点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.