应用转基因小鼠研究心力衰竭的肾上腺素能机制

Adrenergic mechanisms in development of heart failure: progress of studies with transgenic mouse model

Recent progress in the mouse genome and technology for gene manipulations have led to the generation of a rangeof genetic mouse lines with identified cardiac phenotype. Of these, over 20 mouse lines have been developed with targeted genescoding for β- or α-adrenergic receptors(AR ), components of adrenergic signaling transduction pathways and presynapic factorswhich modulate synthesis and release of catecholamines. Meanwhile there has been significant progress in the mousecardiophysiology and miniaturizaion in methods for in vivo functional assessment. In recent years, there have beencomprehensive resereh, using the gene-based mouse lines, on the adrenergic mechanisms in controlling myocardial functionand development of heart failure. Novel findings have been made on the inhibitory cross-talk between α1B-AR and β-AR,cardiomyopathic phenotype of mice that overexpress β1-AN, β2-AR, Gsa or G qa, and inhibitory effect of an enhanced activityof β-AR kinase-1(β ARK1 ) on β-adrenergic signaling and myocardial contractility. A number of inotropic molecules have beenidentified in vivo and, by the novel crossbrecd strategy for gene complementation, ovempression of β2-AR and adenylylcyclase,or expression of βARK1 inhibitor were success in rescuing cardiorvopathic and heart falure phenotypes in several genetic mouselines. These findings from genetic mouse models provide important information on molecular mechanisms of heart failure anddesign of gene therapy.