Myocardial-directed overexpression of the human β₁-adrenergic receptor in transgenic mice

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.