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*

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 Ca-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.

Original languageEnglish (US)
Pages (from-to)42-50
Number of pages9
JournalCirculation research
Volume105
Issue number1
DOIs
StatePublished - Jul 2 2009

Keywords

  • Angiotensin II
  • Calcium exchange
  • Cardiac excitation
  • Contraction coupling
  • Hypertrophy
  • Remodeling
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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