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Early Aldosterone-Regulated Genes in Cardiomyocytes: Clues to Cardiac Remodeling?

Dartmouth Medical School, Department of Physiology, Lebanon, New Hampshire 03756

Address all correspondence and requests for reprints to: Géza Fejes-Tóth, Department of Physiology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, New Hampshire 03756-0001. E-mail: geza.fejes-toth{at}dartmouth.edu.

Recent clinical studies demonstrated beneficial effects of mineralocorticoid receptor (MR) antagonists in patients with heart failure and other cardiovascular diseases. However, the underlying molecular mechanisms are poorly understood, and the genes that mediate direct effects of aldosterone in the cardiovascular system are yet to be identified. The goal of this study was to identify genes that are directly regulated by aldosterone in cardiomyocytes and thus potentially play a role in initiating MR-mediated effects in the heart. We generated clonal cell lines of cardiomyocytes (H9C2 cells) stably expressing the MR. Using these cell lines and Affymetrix microarrays, we determined the effects of physiological concentrations of aldosterone on the gene expression profile. In two independent microarrays we identified 48 genes that were induced more than 1.5-fold (27 known genes and 21 expressed sequence tags) and five (three known genes and two expressed sequence tags) that were suppressed by a 2-h aldosterone treatment. We focused on eight genes that have a potential function in cardiovascular regulation and verified their aldosterone regulation using quantitative RT-PCR. These include genes related to extracellular matrix regulation (tenascin-X, ADAMTS1, PAI-1, UPAR, and hyaluronic acid synthase-2), signaling, and regulation of vascular tone (RGS2, adrenomedullin) and inflammation (orosomucoid). Protein synthesis inhibitors did not prevent aldosterone induction of these genes. We conclude that in cardiomyocytes aldosterone rapidly and directly regulates the expression of several genes that are involved in cardiac remodeling and regulation of blood pressure and thus might be mediators of the physiological and pathophysiological effects of aldosterone on the cardiovascular system.

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