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(Circulation Research. 2009;105:42.)
© 2009 American Heart Association, Inc.

Cellular Biology

Angiotensin II–Mediated Adaptive and Maladaptive Remodeling of Cardiomyocyte Excitation–Contraction Coupling

Konstantin Gusev, Andrea A. Domenighetti, Lea M.D. Delbridge, Thierry Pedrazzini, Ernst Niggli, Marcel Egger

From the Department of Physiology (K.G., E.N., M.E.), University of Bern, Switzerland; Department of Medicine (A.A.D., T.P.), University of Lausanne, Centre Hospitalier Universitaire Vaudois, Switzerland; and Department of Physiology (L.M.D.D.), University of Melbourne, Australia. Present address for A.A.D.: Department of Medicine, University of California at San Diego, La Jolla.

Correspondence to M. Egger, Department of Physiology, University of Bern, Buehlplatz 5, CH-3012 Bern, Switzerland. E-mail egger{at}pyl.unibe.ch

Cardiac hypertrophy is associated with alterations in cardiomyocyte excitation–contraction coupling (ECC) and Ca²⁺ handling. Chronic elevation of plasma angiotensin II (Ang II) is a major determinant in the pathogenesis of cardiac hypertrophy and congestive heart failure. However, the molecular mechanisms by which the direct actions of Ang II on cardiomyocytes contribute to ECC remodeling are not precisely known. This question was addressed using cardiac myocytes isolated from transgenic (TG1306/1R [TG]) mice exhibiting cardiac specific overexpression of angiotensinogen, which develop Ang II–mediated cardiac hypertrophy in the absence of hemodynamic overload. Electrophysiological techniques, photolysis of caged Ca²⁺ and confocal Ca²⁺ imaging were used to examine ECC remodeling at early (20 weeks of age) and late (60 weeks of age) time points during the development of cardiac dysfunction. In young TG mice, increased cardiac Ang II levels induced a hypertrophic response in cardiomyocyte, which was accompanied by an adaptive change of Ca²⁺ signaling, specifically an upregulation of the Na⁺/Ca²⁺ exchanger–mediated Ca²⁺ transport. In contrast, maladaptation was evident in older TG mice, as suggested by reduced sarcoplasmic reticulum Ca²⁺ content resulting from a shift in the ratio of plasmalemmal Ca²⁺ removal and sarcoplasmic reticulum Ca²⁺ uptake. This was associated with a conserved ECC gain, consistent with a state of hypersensitivity in Ca²⁺-induced Ca²⁺ release. Together, our data suggest that chronic elevation of cardiac Ang II levels significantly alters cardiomyocyte ECC in the long term, and thereby contractility, independently of hemodynamic overload and arterial hypertension.

Key Words: cardiac excitation–contraction coupling • remodeling • sodium–calcium exchange • angiotensin II • hypertrophy