Published online before print March 1, 2004, doi: 10.1161/01.CIR.0000121426.43044.2B
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(Circulation. 2004;109:1284-1291.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Aldosterone, Through Novel Signaling Proteins, Is a Fundamental Molecular Bridge Between the Genetic Defect and the Cardiac Phenotype of Hypertrophic Cardiomyopathy
From the Sections of Cardiology and Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Tex.
Reprint requests to A.J. Marian, MD, Baylor College of Medicine, Section of Cardiology, One Baylor Plaza, 519D, Houston, TX 77030. E-mail amarian{at}bcm.tmc.edu
Received December 30, 2003; revision received January 21, 2004; accepted January 29, 2004.
Background— Human hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. The genetic basis of HCM is largely known; however, the molecular mediators of cardiac phenotypes are unknown.
Methods and Results— We show myocardial aldosterone and aldosterone synthase mRNA levels were elevated by 4- to 6-fold in humans with HCM, whereas cAMP levels were normal. Aldosterone provoked expression of hypertrophic markers (NPPA, NPPB, and ACTA1) in rat cardiac myocytes by phosphorylation of protein kinase D (PKD) and expression of collagens (COL1A1, COL1A2, and COL3A1) and transforming growth factor-ß1 in rat cardiac fibroblasts by upregulation of phosphoinositide 3-kinase (PI3K)-p100
. Inhibition of PKD and PI3K-p110 abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor (MR) antagonist spironolactone. Spironolactone reversed interstitial fibrosis, attenuated myocyte disarray by 50%, and improved diastolic function in the cardiac troponin T (cTnT)-Q92 transgenic mouse model of human HCM. Myocyte disarray was associated with increased levels of phosphorylated ß-catenin (serine 38) and reduced ß-catenin–N-cadherin complexing in the heart of cTnT-Q92 mice. Concordantly, distribution of N-cadherin, predominantly localized to cell membrane in normal myocardium, was diffuse in disarrayed myocardium. Spironolactone restored ß-catenin–N-cadherin complexing and cellular distribution of N-cadherin and reduced myocyte disarray in 2 independent randomized studies.
Conclusions— The results implicate aldosterone as a major link between sarcomeric mutations and cardiac phenotype in HCM and, if confirmed in additional models, signal the need for clinical studies to determine the potential beneficial effects of MR blockade in human HCM.
Key Words: cardiomyopathy • myocytes • hypertrophy
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