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

Teng Wu,Tianyi Zhang,Huidi Wang,Mingming Fang,Xiang Lu,Yong Xu,Xiaojun Xin,Yannan Hou

doi:10.3389/fcell.2020.00839

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.

Highlights

Cardiovascular disease (CVD) is the leading cause of deaths worldwide, posing significant health risk and socioeconomic burdens (Cardoso and Nasir, 2019)
In order to assign a cell-specific role for myocardin-related transcription factor A (MRTF-A) in the pathogenesis of cardiac hypertrophy, MRTFA was deleted in cardiomyocytes by removing the floxed Mrtfa allele (Liu et al, 2018) with a Myh6-Cre driver (Yu et al, 2018)
angiotensin II (Ang II) infusion provoked robust hypertrophic response in the murine hearts as evidenced by elevated heart weight/body weight ratios (Figure 1B) and heart weight/tibia bone length ratios (Figure 1C); the conditional knockout (CKO) hearts displayed a much weaker hypertrophic phenotype than the WT hearts. Consistent with these results, echocardiographic measurements showed that augmentation of left ventricular systolic dimension (LVSd) (Figure 1D) and left ventricular posterior wall dimension (LVPWd) (Figure 1E) following Ang II infusion was less prominent in the CKO mice than in the WT mice

Summary

Introduction

Cardiovascular disease (CVD) is the leading cause of deaths worldwide, posing significant health risk and socioeconomic burdens (Cardoso and Nasir, 2019). Heart failure, defined as the inability of the heart to pump blood throughout the body to sustain life activities, is one of the most devastating consequences of CVD (McMurray and Stewart, 2000). A myriad of factors, including hypertension, diabetes, and structural cardiomyopathy, contribute to heart failure (Ziaeian and Fonarow, 2016). Cardiac hypertrophy represents a common intermediate step toward heart failure regardless of etiology (Nakamura and Sadoshima, 2018). Cardiac hypertrophy is initiated as a compensatory response to offset the impairment of heart function following various injurious stimuli. Prolonged and uncontrolled hypertrophic response, further dampens heart function leading up to heart failure

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Results

Conclusion