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An MRTF-A-Sp1-PDE5 Axis Mediates Angiotensin-II-Induced Cardiomyocyte Hypertrophy
Teng Wu1, Huidi Wang1, Xiaojun Xin2
1Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
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.
Insights
Myocardin-related transcription factor A (MRTF-A) plays a key role in cardiac hypertrophy. Targeting the MRTF-A-Sp1-PDE5 pathway may offer new heart failure treatments.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- Cardiac hypertrophy is a key step in heart failure development.
- Multiple signaling pathways regulate cardiomyocyte growth in response to injury.
- Understanding these pathways is crucial for developing heart failure therapies.
Purpose of the Study:
- To investigate the role of MRTF-A in cardiomyocyte-specific cardiac hypertrophy induced by Angiotensin-II (Ang-II).
- To elucidate the underlying molecular mechanisms.
- To identify potential therapeutic targets for heart failure.
Main Methods:
- Conditional knockout mice with cardiomyocyte-specific deletion of MRTF-A.
- In vitro studies using cultured cardiomyocytes with MRTF-A knockdown or inhibition.
- Analysis of gene expression, protein levels, and promoter activity.
- Assessment of cardiac hypertrophy markers.
Main Results:
- Conditional deletion of MRTF-A in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice.
- MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic responses in cultured cardiomyocytes.
- Ang-II upregulated phosphodiesterase 5 (PDE5) expression, which was blocked by MRTF-A manipulation.
- MRTF-A activated Sp1, which bound to the PDE5 promoter, increasing its transcription.
Conclusions:
- A novel MRTF-A-Sp1-PDE5 signaling axis mediates Ang-II-induced cardiac hypertrophy in cardiomyocytes.
- This pathway represents a potential therapeutic target for heart failure.
- Targeting this axis may offer new interventional strategies against heart failure.
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