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Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure

Andrea A Domenighetti1, Qing Wang, Marcel Egger

  • 1Department of Physiology, University of Melbourne, Parkville Victoria, 3010, Australia.

Hypertension (Dallas, Tex. : 1979)
|July 7, 2005
PubMed

Insights

Chronic angiotensin II (Ang II) stimulation directly causes heart muscle cell remodeling and dysfunction, leading to heart failure even without high blood pressure. This study highlights Ang II

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Heart Failure Pathophysiology

Background:

  • Chronic elevation of plasma angiotensin II (Ang II) is known to be detrimental to the heart.
  • Ang II contributes to cardiomyocyte remodeling through both hemodynamic and direct cardiotrophic actions.
  • The sufficiency of direct Ang II actions in causing contractile dysfunction and heart failure, independent of hemodynamic changes, requires clarification.

Purpose of the Study:

  • To investigate the phenotypic changes in cardiomyocytes during adaptive responses to chronic, cardiac-specific, endogenous Ang II stimulation.
  • To determine if direct Ang II actions, without elevated blood pressure, are sufficient to cause heart failure.

Main Methods:

  • Utilized TG1306/1R (TG) mice, which develop Ang II-mediated cardiac hypertrophy without hypertension.
  • Conducted a 94-week longitudinal study assessing cardiac function, cardiomyocyte size, collagen deposition, and calcium handling.
  • Analyzed in vivo cardiac function (dP/dtmax, dP/dtmin) and isolated cardiomyocyte contractility (shortening/lengthening rates).

Main Results:

  • TG mice developed age-dependent dilated cardiomyopathy and increased mortality compared to wild-type (WT) mice.
  • Cardiac hypertrophy in TG mice was associated with cardiomyocyte hypertrophy but not increased collagen deposition.
  • Significant age-dependent systolic and diastolic dysfunction, impaired cardiomyocyte contractility, SERCA2 downregulation, and disrupted calcium transients were observed in TG mice.

Conclusions:

  • Chronic myocardial stimulation by Ang II, even without hemodynamic overload, is sufficient to induce cardiomyocyte hypertrophy and dysfunction.
  • These direct Ang II effects lead to impaired cardiac contractility and calcium homeostasis disturbances.
  • The study concludes that direct Ang II actions can culminate in heart failure.

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