Sympathoadrenergic mechanisms in functional regulation and development of cardiac hypertrophy and failure: findings from genetically engineered mice

Time for primary review 33 days. Sympathoadrenergic signals to the heart are detected and processed by a group of membrane proteins converting external signals to alterations in intracellular properties. In recent years, our understanding of β- and α-adrenergic signaling has been significantly improved. It is beyond the scope of this review to discuss the adrenergic signaling pathways and several excellent reviews are available 1–5. Sympathetic activation serves to maintain cardiac output by enhancing inotropy, relaxation and chronotropy. Under conditions of heart failure (HF), the sympathetic nervous system is activated chronically and enhanced cardiac sympathetic drive frequently precedes the onset of overt clinic symptoms and is one of the fundamental abnormalities in HF 6. In the hypertrophied and failing heart, there occurs profound desensitization of β-adrenergic receptor (AR) signaling due to decreased β1AR density, uncoupling of βAR to stimulatory G-protein (Gs), diminished adenylyl cyclase (AC) activity, increased βAR kinase (βARK) activity, and elevated content and function of inhibitory G-protein (Gi) 1, 4, 7. The pathophysiological implications of these alterations are only partially understood. Numerous mouse strains have recently been created that target key components in the signaling pathways as well as these components involved in sympathetic activity (Table 1) 8–47. These genes are either overexpressed in the heart, mostly under the α-myosin heavy chain promoter, or are disrupted or modified. These strains provide us with systematic tools and novel opportunities to address a number of fundamental questions crucial to our understanding of the contribution by the sympathoadrenergic system to cardiac physiology and pathophysiology. These questions include the difference in signaling mediated by β1AR and β2AR, roles of βARK1 in βAR signaling and functional regulation, activities of α1AR subtypes in cardiac function and hypertrophic growth, contributions of heterotrimeric G-proteins (like Gq and … * Tel.: +61-3-9522-4333; fax: +61-3-9521-1362 xiaojun. duatbaker. edu. au