Myocardin-related transcription factor A regulates integrin beta 2 transcription to promote macrophage infiltration and cardiac hypertrophy in mice
Myocardin-related transcription factor A regulates integrin beta 2 transcription to promote macrophage infiltration and cardiac hypertrophy in mice
复制标题
心肌素相关转录因子A调节整合素β2转录促进小鼠巨噬细胞浸润和心脏肥大
DOI：
10.1093/cvr/cvab110
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发表时间：
2021-04-10
影响因子：
10.8
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Liu, Li;Zhao, Qianwen;Xu, Yong
Aims Macrophage-mediated inflammatory response represents a key pathophysiological process in a host of cardiovascular diseases including heart failure. Regardless of aetiology, heart failure is invariably preceded by cardiac hypertrophy. In the present study, we investigated the effect of macrophage-specific deletion of myocardin-related transcription factor A (MRTF-A) on cardiac hypertrophy and the underlying mechanism. Methods and results We report that when subjected to transverse aortic constriction (TAC), macrophage MRTF-A conditional knockout (CKO) mice developed a less severe phenotype of cardiac hypertrophy compared to wild-type (WT) littermates and were partially protected from the loss of heart function. In addition, there was less extensive cardiac fibrosis in the CKO mice than WT mice following the TAC procedure. Further analysis revealed that cardiac inflammation, as assessed by levels of pro-inflammatory cytokines and chemokines, was dampened in CKO mice paralleling reduced infiltration of macrophages in the heart. Mechanistically, MRTF-A deficiency attenuated the expression of integrin beta 2 (ITGB2/CD18) in macrophage thereby disrupting adhesion of macrophages to vascular endothelial cells. MRTF-A was recruited by Sp1 to the ITGB2 promoter and cooperated with Sp1 to activate ITGB2 transcription in macrophages. Administration of a CD18 blocking antibody attenuated TAC-induced cardiac hypertrophy in mice. Interaction between MRTF-A and the histone demethylase KDM3A likely contributed to IGTB2 transcription and consequently adhesion of macrophages to endothelial cells. Conclusions Our data suggest that MRTF-A may regulate macrophage trafficking and contribute to the pathogenesis of cardiac hypertrophy by activating ITGB2 transcription.
