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

Details

Serval ID
serval:BIB_063999F40749
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Angiotensin II-mediated phenotypic cardiomyocyte remodeling leads to age-dependent cardiac dysfunction and failure
Journal
Hypertension
Author(s)
Domenighetti  A. A., Wang  Q., Egger  M., Richards  S. M., Pedrazzini  T., Delbridge  L. M.
ISSN
1524-4563 (Electronic)
Publication state
Published
Issued date
08/2005
Volume
46
Number
2
Pages
426-32
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Aug
Abstract
Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II-mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (approximately 45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.
Keywords
*Aging Angiotensin II/*metabolism Angiotensinogen/genetics Animals Calcium/metabolism Calcium-Transporting ATPases/metabolism Cardiac Output, Low/*etiology/mortality Cardiomegaly/etiology/pathology Cardiomyopathy, Dilated/*etiology/mortality/pathology/*physiopathology Male Mice Mice, Transgenic Myocardial Contraction Myocardium/pathology *Myocytes, Cardiac/metabolism Myosin Heavy Chains/genetics Phenotype Promoter Regions (Genetics) Rats Sarcoplasmic Reticulum Calcium-Transporting ATPases *Ventricular Remodeling
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 8:45
Last modification date
20/08/2019 12:28
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