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

Abstract

Abstract-Cardiac hypertrophy is associated with alterations in cardiomyocyte excitation-contraction coupling (ECC) and Ca 2ϩ 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 Ca 2ϩ and confocal Ca 2ϩ imaging were used to examine ECC remodeling at early (Ϸ20 weeks of age) and late (Ϸ60 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 Ca 2ϩ signaling, specifically an upregulation of the Na ϩ /Ca 2ϩ exchangermediated Ca 2ϩ transport. In contrast, maladaptation was evident in older TG mice, as suggested by reduced sarcoplasmic reticulum Ca 2ϩ content resulting from a shift in the ratio of plasmalemmal Ca 2ϩ removal and sarcoplasmic reticulum Ca 2ϩ uptake. This was associated with a conserved ECC gain, consistent with a state of hypersensitivity in Ca 2ϩ -induced Ca 2ϩ 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 Ⅲ remodeling Ⅲ sodium-calcium exchange Ⅲ angiotensin II Ⅲ hypertrophy H ypertension is a major risk factor for the genesis and progression of a variety of cardiovascular diseases including heart failure, stroke, and kidney dysfunction. Common therapies for the treatment of hypertension lower blood pressure via inhibition of the renin-angiotensin system (RAS). Drugs include inhibitors of the angiotensinconverting enzyme, as well as angiotensin II (Ang II) receptor type 1 (AT 1 ) antagonists, thus preventing the formation of Ang II or its binding to AT 1 receptors. 1,2 In addition to its effects on the vasculature, the RAS plays an important role in the development of cardiac hypertrophy. 3 Sustained activation of the RAS results in arterial hypertension, which in turn produces hemodynamic overload. The adaptation of the heart to this loading is characterized by a change in cardiac protein expression and substantial cardiac remodeling. In addition, Ang II also exerts direct growth-promoting effects on cardiac tissues, resulting in cardiomyocyte hypertrophy and mechanical dysfunction independently of hypertension. 4,5 Ang II activates several intracellular signal transduction pathways including mitogen-activated protein kinases and protein kinase C. 6,7 Therefore,...

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