Angiotensin II-mediated adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling.
Cardiac hypertrophy is associated with alterations in cardiomyocyte excitation-contraction coupling (ECC) and Ca(2+) 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(2+) and confocal Ca(2+) imaging were used to examine ECC remodeling at early ( approximately 20 weeks of age) and late ( approximately 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 Ca(2+) signaling, specifically an upregulation of the Na(+)/Ca(2+) exchanger-mediated Ca(2+) transport. In contrast, maladaptation was evident in older TG mice, as suggested by reduced sarcoplasmic reticulum Ca(2+) content resulting from a shift in the ratio of plasmalemmal Ca(2+) removal and sarcoplasmic reticulum Ca(2+) uptake. This was associated with a conserved ECC gain, consistent with a state of hypersensitivity in Ca(2+)-induced Ca(2+) 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.
Gusev
Konstantin
K
Department of Physiology, University of Bern, Switzerland.
Domenighetti
Andrea A
AA
Delbridge
Lea M D
LM
Pedrazzini
Thierry
T
Niggli
Ernst
E
Egger
Marcel
M
D000804:Angiotensin II / Q000502:physiology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D006332:Cardiomegaly; D022062:Electrophysiologic Techniques, Cardiac; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology*; D019831:Sodium-Calcium Exchanger
D019831:Sodium-Calcium Exchanger; D000808:Angiotensinogen; D000804:Angiotensin II; D002118:Calcium