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[摘要]：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 (approximate to 20 weeks of age) and late (approximate to 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. (Circ Res. 2009; 105: 42-50.) |
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