Transgenic mice with cardiac overexpression of alpha(1B)-adrenergic receptors - In vivo alpha(1)-adrenergic receptor-mediated regulation of beta-adrenergic signaling

Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha(1B)-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter, Previously, we described transgenic mice with alpha-myosin heavy chain-directed expression of a constitutively active mutant alpha(1B)-AR that had a phenotype of myocardial hypertrophy (Milano, C, A., Dolber, P. C,, Rockman, H. A., Bond, R. A., Venable M, E,, Alien, L, F,, and Lefkowitz, R, J. (1994) Proc. Natl. Acad. Sci. U,S. A, 91, 10109-10113). In animals with >40-fold WT alpha(1)-AR overexpression, basal myocardial diacylglycerol content was significantly increased, indicating enhanced alpha(1)-adrenergic signaling and phospholipase C activity, In contrast to the mice overexpressing constitutively active mutant alpha(1B)-ARs, the hearts of these mice did not develop cardiac hypertrophy despite an 8-fold increase in ventricular mRNA for atrial natriuretic factor, In vivo physiology was studied in anesthetized intact animals and showed left ventricular contractility in response to the beta-agonist isoproterenol to be significantly depressed in animals overexpressing WT alpha(1B).ARs, Membranes purified from the hearts of WT alpha(1B).AR-overexpressing mice demonstrated significantly attenuated adenylyl cyclase activity basally and after stimulation with isoproterenol, norepinephrine, or phenylephrine, Interestingly, these in vitro changes in signaling were reversed after treating the mice with pertussis toxin, suggesting that the extraordinarily high levels of WT alpha(1B).ARs can lead to coupling to pertussis toxin-sensitive G proteins, Another potential contributor to the observed decreased myocardial signaling and function could be enhanced beta-AR desensitization as beta-adrenergic receptor kinase (beta ARK1) activity was found to be significantly elevated (>3-fold) in myocardial extracts isolated from WT alpha(1B)-AR-overexpressing mice, This type of altered signal transduction may become critical in disease conditions such as heart failure where beta ARK1 levels are elevated and beta-ARs are downregulated, leading to a higher percentage of cardiac alpha(1).Ars. Thus, these mice serve as a unique experimental model to study the in vivo interactions between alpha- and beta-ARs in the heart.