Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene

doi:10.1073/pnas.0307333101

Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene

^*Departments of Pathology and Laboratory Medicine, and ^‡Department of Medicine, Division of Cardiology, University of North Carolina, Chapel Hill, NC 27599; and ^§Department of Medicine, Duke University Medical Center, Durham, NC 27710

Contributed by Oliver Smithies, December 31, 2003

Abstract

Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males develop concentric cardiac hypertrophy with fibrosis but without dilatation. Over half die suddenly aged 6-8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Expression of seven hypertrophy-related genes in this and two categorically different models (lack of atrial natriuretic peptide receptor A; overexpression of calsequestrin) were compared. Statistical analyses show that ventricular expressions of the genes coding for atrial natriuretic peptide, β myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin correlate equally well with the degree of hypertrophy, although their ranges of expression are, respectively, 50-, 30-, 10-, and 3-fold.

Footnotes

↵ ¶ To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, CB 7525, 701 Brinkhous-Bullitt Building, University of North Carolina, Chapel Hill, NC 27599-7525. E-mail: jenny_langenbach{at}med.unc.edu.
↵ † K.M.I.C. and L.R.J. contributed equally to this work.
Abbreviations: AM, adrenomedullin; Ang, angiotensin; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; BP, blood pressure; BW, body weight; MCAD, medium chain acyl-CoA dehydrogenase; MHC, myosin heavy chain; TGF, transforming growth factor.