An MRTF-A–Sp1–PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy

Abstract

Cardiac hypertrophy is a critical intermediate step in the pathogenesis of heart failure. A myriad of signaling networks converge on cardiomyocytes to elicit hypertrophic growth in response to various injurious stimuli. In the present study, we investigated the cardiomyocyte-specific role of myocardin-related transcription factor A (MRTF-A) in angiotensin-II (Ang-II)-induced cardiac hypertrophy and the underlying mechanism. We report that conditional MRTF-A deletion in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice. Similarly, MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic response in cultured cardiomyocytes. Of note, Ang II treatment upregulated expression of phosphodiesterase 5 (PDE5), a known mediator of cardiac hypertrophy and heart failure, in cardiomyocytes, which was blocked by MRTF-A depletion or inhibition. Mechanistically, MRTF-A activated expression of specificity protein 1 (Sp1), which in turn bound to the PDE5 promoter and upregulated PDE5 transcription to promote hypertrophy of cardiomyocytes in response to Ang II stimulation. Therefore, our data unveil a novel MRTF-A-Sp1-PDE5 axis that mediates Ang-II-induced hypertrophic response in cardiomyocytes. Targeting this newly identified MRTF-A-Sp1-PDE5 axis may yield novel interventional solutions against heart failure.

Myeloid MKL1 Disseminates Cues to Promote Cardiac Hypertrophy in Mice

“…It has also been shown that ablation of miR-155 in cardiomyocytes appears to be sufficient to blunt the hypertrophic response induced by phenoephrine (PE) ( Seok et al, 2014 ). This alternative model wherein MKL1 activates miR-155 transcription in cardiomyocytes to promote cardiac hypertrophy is certainly tempting in light of our recent report that cardiomyocyte-specific MKL1 deletion attenuates angiotensin II induced cardiac hypertrophy in mice ( Wu et al, 2020 ). Second, the finding that MKL1 relies on NF-κB to regulate miR-155 transcription reinforces the notion that MKL1 and NF-κB are functionally interconnected given previous investigations linking these two factors in the pathogenesis of atherosclerosis ( Fang et al, 2011 ), colitis ( Yu et al, 2014 ), and septic shock ( Yu et al, 2017 ), However, the precise role of NF-κB in the pathogenesis of cardiac hypertrophy has not been conclusively demonstrated especially in animal models likely due to the isoform-specific effects of NF-κB ( Gordon et al, 2011 ).…”

“…Endothelin (ET-1) was purchased from Peprotech. CCG-1423 ( Chen et al, 2020a ; Wu et al, 2020 ) and PDTC ( Xu et al, 2017 ) were purchased from Selleck. MKL1 expression constructs and miR-155 promoter-luciferase constructs have been described previously ( Basso et al, 2012 ; Thompson et al, 2013 ; Li et al, 2019c ).…”

BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

“…Transient transfections were performed with Lipofectamine 2000. Luciferase activities were assayed 24–48 h after transfection using a luciferase reporter assay system (Promega) as previously described ( Wu et al, 2020 ; Yang et al, 2020a,b ). For conditioned media (CM) collection, the cells were switched to and incubated with serum-free media overnight.…”

BRG1 Links TLR4 Trans-Activation to LPS-Induced SREBP1a Expression and Liver Injury

“…Chromatin immunoprecipitation (ChIP) assays were performed essentially as described before ( Chen et al, 2020a , b , c ; Dong et al, 2020 ; Fan et al, 2020 ; Li et al, 2020a , b , c ; Lv et al, 2020 ; Mao et al, 2020 ; Sun et al, 2020 ; Wu et al, 2020 ; Yang et al, 2020 ). In brief, chromatin in control and treated cells were cross-linked with 1% formaldehyde.…”