Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn230
Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction
a BHF Heart Research Unit, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, UK
b Molecular Medicine, St. James's University Hospital, Leeds, UK
c Division of Cardiovascular and Diabetes Research, LIGHT, University of Leeds, UK
* Corresponding author: JFX Ainscough, BHF Heart Research Unit, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, LS2 9JT, UK Tel: +44 113 343 4168, Fax: +44 113 343 4803, Email: medjfxa{at}leeds.ac.uk
Aims: Sustained hypertension leads to cardiac hypertrophy that can progress, through pathological remodelling, to heart failure. Abnormality of the renin-angiotensin system has been strongly implicated in this process. Although hypertrophy in man is an established risk factor independent of blood pressure, separation of remodelling in response to local cues within the differentiated myocardium from that related to pressure overload is unresolved. The present study aimed to clarify the role of local renin-angiotensin system activity specifically in the adult heart, in modulating cardiac hypertrophy and pathological remodelling.
Methods: Transgenic mice with inducible cardiomyocyte-specific expression of a wild-type or N111G mutant form of the human angiotensin II type-1 receptor (hAT1R) were generated. The wild-type receptor is primarily stimulated by angiotensin II (Ang II). In contrast, the N111G receptor can also be fully stimulated by the Ang II derivative, Ang IV, at levels that do not stimulate the wild-type receptor. The unique properties of these models were used to investigate the myocardial growth, remodelling and functional responses to hAT1R stimulation specifically in adult cardiomyocytes, under normal conditions and following Ang IV infusion.
Results: Low-level expression of wild-type or N111G hAT1R at the cardiomyocyte membrane, from onset of adolescence, induced enhanced myocyte growth and associated cardiac hypertrophy in the adult. This was not associated with change in resting blood pressure or heart rate, measured by longitudinal telemetric analysis, and did not progress to pathological remodelling or heart failure. However, selective activation of cardiomyocyte-specific N111G receptors by Ang IV peptide infusion induced adverse ventricular remodelling within 4-weeks. This was characterised by increased interstitial fibrosis, dilatation of the left ventricle and impaired cardiac function.
Conclusions: Low level local AT1R activity in differentiated myocardium causes compensated cardiac hypertrophy, that is increased myocardial mass but with retention of normal function, while short term increased stimulation induces cardiac dysfunction with dilatation, reduced ejection fraction and increased fibrosis in the absence of change in systemic blood pressure.
KEYWORDS Angiotensin II type-1 receptor; blood pressure; cardiomyocyte; remodelling; transgenic mouse
Time for primary review: 25 days
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