DISTINCT ROLE OF ADRENOCEPTOR SUBTYPES IN CARDIAC ADAPTATION TO CHRONIC PRESSURE OVERLOAD

SUMMARY1 With the generation of gene knockout (KO) or transgenic overexpression (TG) mouse models targeting adrenoceptors (AR), recent studies in vivo have investigated the role of AR subtypes in pressure overload‐induced left ventricular (LV) hypertrophy and remodelling. 2 Although subjecting α 1B ‐KO mice to transverse aortic constriction (TAC) did not reveal significant phenotype differences compared with controls, mice deficient in both α 1A ‐ and α 1B ‐AR responded to TAC with poor survival, increased cardiomyocyte apoptosis, more severe fibrosis and dysfunction, but a similar degree of LV hypertrophy, compared with wild‐type littermates. Following TAC, α 1B ‐TG mice developed more severe hypertrophy, interstitial fibrosis and LV dysfunction. In contrast, overexpression of α 1A ‐AR preserved cardiac function and reduced death from heart failure without affecting the degree of LV hypertrophy. Thus, α 1A ‐ and α 1B ‐adrenoceptor signalling impacts differently on myocardial adaptation to pressure overload. 3 The absence of both β 1 ‐ and β 2 ‐AR significantly suppressed pressure overload‐evoked hypertrophy, fibrosis and expression of inflammatory or fibrogenic genes. Conversely, studies on β 2 ‐TG mice with TAC revealed adverse consequences, including accelerated development of heart failure, poor survival and more severe interstitial fibrosis, but a comparable degree of hypertrophy compared with wild‐type littermates. 4 Collectively, these findings suggest that the effect of ARs on pressure overload‐induced myocardial adaptation is subtype specific. Whereas activation of α 1B ‐AR or β 2 ‐AR contributes to maladaptation and the onset of heart failure, activation of α 1A ‐AR or inactivation of β 2 ‐AR is beneficial in the setting of chronic pressure overload.