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(Circulation. 2005;112:2307-2317.)
© 2005 American Heart Association, Inc.

Hypertension

Enhanced Activity of the Myocardial Na⁺/H⁺ Exchanger NHE-1 Contributes to Cardiac Remodeling in Atrial Natriuretic Peptide Receptor–Deficient Mice

Ana Kilic, PhD; Ana Velic, PhD; León J. De Windt, PhD; Larissa Fabritz, MD; Melanie Voss; Danuta Mitko; Melanie Zwiener, DVM; Hideo A. Baba, MD; Martin van Eickels, MD; Eberhard Schlatter, PhD; Michaela Kuhn, MD

From the Institute of Physiology, University of Würzburg (A.K., M.K.), Würzburg, Germany; the Institute of Pharmacology and Toxicology (A.K., M.V., D.M., M.K.), the Department of Internal Medicine D, Experimental Nephrology (A.V., E.S.), the Department of Cardiology and Angiology (L.F., M.Z.), and Interdisciplinary Center for Clinical Research, University of Münster (A.K., A.V., L.F., M.Z., E.S., M.K.), Münster, Germany; the Institute of Pathology, University of Duisburg-Essen (H.A.B.), Duisburg-Essen, Germany; TD Cardiovascular Diseases, Sanofi-Aventis (M.v.E.), Frankfurt, Germany; and Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht (L.J.D.W.), The Netherlands.

Correspondence to Michaela Kuhn, Physiologisches Institut der Universität Würzburg, Röntgenring 9, D - 97070 Würzburg, Germany. E-mail michaela.kuhn{at}mail.uni-wuerzburg.de

Received February 10, 2005; revision received July 14, 2005; accepted July 19, 2005.

Background— Atrial natriuretic peptide (ANP), through its guanylyl cyclase-A (GC-A) receptor, not only is critically involved in the endocrine regulation of arterial blood pressure but also locally moderates cardiomyocyte growth. The mechanisms underlying the antihypertrophic effects of ANP remain largely uncharacterized. We examined the contribution of the Na⁺/H⁺ exchanger NHE-1 to cardiac remodeling in GC-A–deficient (GC-A^–/–) mice.

Methods and Results— Fluorometric measurements in isolated adult cardiomyocytes demonstrated that cardiac hypertrophy in GC-A^–/– mice was associated with enhanced NHE-1 activity, alkalinization of intracellular pH, and increased Ca²⁺ levels. Chronic treatment of GC-A^–/– mice with the NHE-1 inhibitor cariporide normalized cardiomyocyte pH and Ca²⁺ levels and regressed cardiac hypertrophy and fibrosis, despite persistent arterial hypertension. To characterize the molecular pathways driving cardiac hypertrophy in GC-A^–/– mice, we evaluated the activity of 4 prohypertrophic signaling pathways: the mitogen-activated protein kinases (MAPK), the serine-threonine kinase Akt, calcineurin, and Ca²⁺/calmodulin-dependent kinase II (CaMKII). The results demonstrate that all 4 pathways were activated in GC-A^–/– mice, but only CaMKII and Akt activity regressed during reversal of the hypertrophic phenotype by cariporide treatment. In contrast, the MAPK and calcineurin/NFAT signaling pathways remained activated during regression of hypertrophy.

Conclusions— On the basis of these results, we conclude that the ANP/GC-A system moderates the cardiac growth response to pressure overload by preventing excessive activation of NHE-1 and subsequent increases in cardiomyocyte intracellular pH, Ca²⁺, and CaMKII as well as Akt activity.

Key Words: hypertension • natriuretic peptides • hypertrophy • calcineurin • sodium-hydrogen antiporter

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