Cardiac hypertrophy is associated with alterations in cardiomyocyte excitation-contraction coupling (ECC) and Ca²⁺ handling. Chronic elevation of plasma angiotensin II (AngII) is a major determinant in the pathogenesis of cardiac hypertrophy and congestive heart failure. However, the molecular mechanisms by which the direct actions of AngII on cardiomyocytes contribute to ECC remodeling are not precisely known. AngII activates several intracellular signal transduction pathways including mitogen-activated protein kinases (MAPK) and protein kinase C (PKC). Therefore, a local increase in the AngII concentration can contribute significantly to the pathogenesis of cardiac hypertrophy, even in the absence of arterial hypertension.

This question was addressed in cardiac myocytes isolated from transgenic mice (TG1306/1R, TG) with cardiac specific overexpression of angiotensinogen, which develop AngII-mediated cardiac hypertrophy in the absence of hemodynamic overload. TG mice carry multiple copies of the rat angiotensinogen gene under control of the cardiac-specific a-myosin heavy chain (a-MHC) promoter, leading to elevated cardiac angiotensinogen levels. As a consequence, AngII concentrations in the heart of TG mice are increased whereas plasma AngII level, and therefore blood pressure, remain unchanged. Thus, the mice develop AngII-mediated cardiac hypertrophy in the absence of high blood pressure. Electrophysiological techniques, photolysis of caged Ca²⁺ and confocal Ca²⁺ imaging were used to examine ECC remodeling at an early (around 20 weeks of age) and late (around 60 weeks of age) time points during the development of cardiac dysfunction. In young TG, increased cardiac AngII 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 (NCX) mediated Ca²⁺ transport. In contrast, maladaptation was evident in older TG as suggested by reduced sarcoplasmic reticulum (SR)-Ca²⁺ content due to a shift in the ratio of plasmalemmal Ca²⁺ removal and SR-Ca²⁺ uptake. This was associated with a conserved ECC gain, consistent with a state of hypersensitivity of the Ca²⁺-induced Ca²⁺ release mechanism and may represent a primary ECC lesion in the progression to heart failure. Our data emphasize the importance of aging and disease progression on ECC dysfunction and subsequent functional decompensation at the organ level.

The present study supports an important role for AngII in the regulation of Ca²⁺ handling protein expression and activity, and suggests that enhancement of cardiac contractility might be achieved by modulating cardiomyocyte AngII signaling.