ArticleProceedings of the National Academy of Sciences of the United States of America2016
Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 49 citations in OpenAlex.
- Cardiac fibroblast Foxm1 deficiency prevents pressure overload-induced cardiac remodeling via the Usp10/MKK6-p38γ MAPK axis.Cell death and differentiation · 2026Review
- Article
- Cardiac-specific deletion of BRG1 ameliorates ventricular arrhythmia in mice with myocardial infarction.Acta pharmacologica Sinica · 2024Article
- ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification.Journal of biomedical science · 2023Review
- Restoration of the gut barrier integrity and restructuring of the gut microbiome in aging by angiotensin-(1-7).Clinical science (London, England : 1979) · 2023Article
- FOXM1: Functional Roles of FOXM1 in Non-Malignant Diseases.Biomolecules · 2023Review
- Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis.International journal of molecular sciences · 2023Article
- Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells.Acta pharmacologica Sinica · 2022Article
- Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis.Trends in molecular medicine · 2022Review
- Variable susceptibility of intestinal organoid-derived monolayers to SARS-CoV-2 infection.PLoS biology · 2022Article
- Endothelial-Mesenchymal Transition or Functional Tissue Regeneration - Two Outcomes of Heart Remodeling.Physiological research · 2021Review
- The Elabela-APJ axis: a promising therapeutic target for heart failure.Heart failure reviews · 2021Review
- Clinical impact of echocardiography parameters and molecular biomarkers in heart failure: Correlation ofExperimental and therapeutic medicine · 2021Article
- ACE2/ACE imbalance and impaired vasoreparative functions of stem/progenitor cells in aging.GeroScience · 2021Article
- FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation.Cell death & disease · 2021Article
- From bedside to bench: regulation of host factors in SARS-CoV-2 infection.Experimental & molecular medicine · 2021Review
- Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake.Frontiers in pharmacology · 2021Article
- Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19.Journal of molecular and cellular cardiology · 2020Article
- Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection.bioRxiv : the preprint server for biology · 2020Article
- Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence.Journal of clinical medicine · 2020Review
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Genes encoding angiotensin-converting enzymes (Ace and Ace2) are essential for heart function regulation. Cardiac stress enhances Ace, but suppresses Ace2, expression in the heart, leading to a net production of angiotensin II that promotes cardiac hypertrophy and fibrosis. The regulatory mechanism that underlies the Ace2-to-Ace pathological switch, however, is unknown. Here we report that the Brahma-related gene-1 (Brg1) chromatin remodeler and forkhead box M1 (FoxM1) transcription factor cooperate within cardiac (coronary) endothelial cells of pathologically stressed hearts to trigger the Ace2-to-Ace enzyme switch, angiotensin I-to-II conversion, and cardiac hypertrophy. In mice, cardiac stress activates the expression of Brg1 and FoxM1 in endothelial cells. Once activated, Brg1 and FoxM1 form a protein complex on Ace and Ace2 promoters to concurrently activate Ace and repress Ace2, tipping the balance to Ace2 expression with enhanced angiotensin II production, leading to cardiac hypertrophy and fibrosis. Disruption of endothelial Brg1 or FoxM1 or chemical inhibition of FoxM1 abolishes the stress-induced Ace2-to-Ace switch and protects the heart from pathological hypertrophy. In human hypertrophic hearts, BRG1 and FOXM1 expression is also activated in endothelial cells; their expression levels correlate strongly with the ACE/ACE2 ratio, suggesting a conserved mechanism. Our studies demonstrate a molecular interaction of Brg1 and FoxM1 and an endothelial mechanism of modulating Ace/Ace2 ratio for heart failure therapy.
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