Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex.
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.
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202;
Jin
J
Yang
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202;
Xuhui
X
Feng
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202;
Qiong
Q
Zhou
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202;
Wei
W
Cheng
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Ching
C
Shang
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Pei
P
Han
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Chiou-Hong
CH
Lin
Del E. Webb Neuroscience, Aging, and Stem Cell Research Center, Sanford/Burnham Medical Research Institute, La Jolla, CA 92037.
Huei-Sheng Vincent
HS
Chen
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Thomas
T
Quertermous
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202; changcp@iu.edu.
Ching-Pin
CP
Chang
D000804:Angiotensin II / Q000096:biosynthesis / Q000235:genetics; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D013883:Thiostrepton / Q000008:administration & dosage; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D000072278:Forkhead Box Protein M1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; D000804:Angiotensin II; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D013883:Thiostrepton
Brg1; FoxM1; cardiac hypertrophy; chromatin remodeling; endothelial cells