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

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.