Myocardial-directed overexpression of the human beta(1)-adrenergic receptor in transgenic mice

The beta(1)-adrenergic receptor (AR) is the dominant subtype in non-failing and Failing myocardium. beta(1)-AR signaling, by the endogenous neurotrans mitter norepinephrine, is central to the regulation of myocardial contracti lity. In heart failure, the beta(1)-AR undergoes subtype-selective downregu lation which may protect, against the increased cardiac adrenergic drive as sociated with this pathophysiological stale. To examine the hypothesis that chronically increased beta(1)-AR mediated signaling has adverse myocardial effects, transgenic mice overexpressing the human beta(1)-AR in a cardiac- selective context were produced, utilizing an alpha-myosin heavy chain (MHC ) promoter. In these mice, beta(1)-AR protein abundance was similar to 24-4 6-fold (1-2 pmol/mg protein) that of wild-type mice. Histopathological examination of young (4 months old) and old (greater than or equal to 9 months old) transgenic mouse hearts consistently demonstrate d large areas of interstitial replacement fibrosis, marked myocyte hypertro phy and myofibrilar disarray. In addition, increased expression of the pre- apoptotic marker. Bax, was observed coincident with regions of fibrosis acc ompanied by an increased apoptotic index, as measured by TUNEL assay. Older non-transgenic mice exhibited a slight tendency towards a decreased f ractional shortening, whereas older beta(1)-AR transgenic mice had a marked reduction in fractional shortening (%FS similar to 30) as determined by ec hocardiography. Additionally, older beta(1)-AR transgenic mice had an incre ased left ventricular chamber size. In summary, cardiac-directed overexpression of the human beta(1)-AR in tran sgenic mice leads to a significant histopathological phenotype with no appa rent functional consequence in younger mice and a variable degree of cardia c dysfunction in older animals. This model system may ultimately prove usef ul for investigating the biological basis of adrenergically-mediated myocar dial damage in humans. (C) 2000 Academic Press.