The β1-adrenergic receptor (AR) is the dominant subtype in non-failing and failing myocardium. β1-AR signaling, by the endogenous neurotransmitter norepinephrine, is central to the regulation of myocardial contractility. In heart failure, the β1-AR undergoes subtype-selective downregulation which may protect against the increased cardiac adrenergic drive associated with this pathophysiological state. To examine the hypothesis that chronically increased β1-AR mediated signaling has adverse myocardial effects, transgenic mice overexpressing the human β1-AR in a cardiac-selective context were produced, utilizing an α-myosin heavy chain (MHC) promoter. In these mice, β1-AR protein abundance was -24-46-fold (1-2 pmol/mg protein) that of wild-type mice. Histopathological examination of young (4 months old) and old (≥ 9 months old) transgenic mouse hearts consistently demonstrated large areas of interstitial replacement fibrosis, marked myocyte hypertrophy and myofibrilar disarray. In addition, increased expression of the pre-apoptotic marker, Bax, was observed Coincident with regions of fibrosis accompanied by an increased apoptotic index, as measured by TUNEL assay. Older non-transgenic mice exhibited a slight tendency towards a decreased fractional shortening, whereas older β1-AR transgenic mice had a marked reduction in fractional shortening (%FS -30) as determined by echocardiography. Additionally, older β1-AR transgenic mice had an increased left ventricular chamber size. In summary, cardiac-directed overexpression of the human β1-AR in transgenic mice leads to a significant histopathological phenotype with no apparent functional consequence in younger mice and a variable degree of cardiac dysfunction in older animals. This model system may ultimately prove useful for investigating the biological basis of adrenergically-mediated myocardial damage in humans. (C) 2000 Academic Press.
Bibliographical noteFunding Information:
We wish to thank Drs Walter Koch, Robert Lef-kowitz, Leslie Leinwand and Karen Vikstrom for many helpful discussions about transgenic mice and adrenergic receptor biology. We would also like to thank Dr Jeffrey Robins for providing us with the α-MHC promoter-containing vector, pNC1. This work was supported in large part by the Temple Hoyne Buell Endowment to the Division of Cardiology at the UCHSC. Transgenic mice were produced at the University of Colorado HSC transgenic mouse Core Facility which is subsidized by the University of Colorado Cancer Center.
Copyright 2017 Elsevier B.V., All rights reserved.
- Beta adrenergic receptors
- Heart failure
- Transgenic mice