| First Author | Cho MC | Year | 1999 |
| Journal | Circulation | Volume | 99 |
| Issue | 20 | Pages | 2702-7 |
| PubMed ID | 10338466 | Mgi Jnum | J:55312 |
| Mgi Id | MGI:1337704 | Doi | 10.1161/01.cir.99.20.2702 |
| Citation | Cho MC, et al. (1999) Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine. Circulation 99(20):2702-7 |
| abstractText | Background-Elevated circulating norepinephrine (NE) has been implicated in causing the profound beta-adrenergic receptor (beta AR) downregulation and receptor uncoupling that are characteristic of end-stage human dilated cardiomyopathy, a process mediated in part by increased levels of beta-adrenergic receptor kinase (beta ARK1). To explore whether chronic sustained NE stimulation is a primary stimulus that promotes deterioration in cardiac signaling, wt characterized a gene-targeted mouse in which activation of the sympathetic nervous system cannot lead to an elevation in plasma NE and epinephrine. Methods ann Results-Gene-targeted mice that lack dopamine beta-hydroxylase (dbh(-/-)), the enzyme needed to convert dopamine to NE, were created by homologous recombination. In vivo contractile response to the beta(1)AR agonist dobutamine, measured by a high-fidelity left ventricular micromanometer, was enhanced in mice lacking the dbh gene. In unloaded adult myocytes isolated from dbh(-/-) mice, basal contractility was significantly increase compared with control cells. Furthermore, the increase in beta AR responsiveness and enhanced cellular contractility were associated with a significant reduction in activity and protein level of beta ARK1 and increased high-affinity agonist binding without changes in beta AR density or G- protein levels. Conclusions Nice that lack the ability to generate NE or epinephrine show increased contractility associated primarily with a decrease in the level of beta ARK1 protein and kinase activity. This animal model will be valuable in testing whether NE is required for the pathogenesis of heart failure through mating strategies that cross the dbh(-/-) mouse into genetically engineered models of heart failure. |
