Overexpression of β2AR improves contractile function and cellular survival in rabbit cardiomyocytes under chronic hypoxia

Chronic hypoxia usually evokes sustained release of endogenous neurohormones, leading to β2-adrenergic receptor (β2AR) desensitization and downregulation of expression, which impacts cellular contractility. We investigated whether exogenous β2AR could compensate for the functional deficiency of β2AR in rabbit cardiomyocytes under chronic hypoxia, and whether this led to improved contractility and cellular survival.A surgical experimental model of cyanotic heart disease was established in rabbits. Adv.hβ2AR was transfected into cardiomyocytes isolated from animals subjected to 6-week systemic hypoxia. The levels of cellular contractile function, protein expression of hβ2AR, p-Akt, p-Erk, and caspase-3, and cellular survival pre- and post-Adv.hβ2AR delivery were determined.In the cyanotic cells, decreased shortening and lengthening of TPC and R50 were evident. Cellular diastolic functioning showed greater deterioration compared to the systolic function (P < 0.05). In cyanotic cells, the positive inotropic response to isoproterenol was decreased (P < 0.01), low levels of cellular survival were found, protein levels of β2AR, p-Akt, and p-Erk were downregulated, and protein levels of caspase-3 were upregulated. After Adv.hβ2AR delivery, enhanced contractile function was achieved (P < 0.01), TPC and R50 levels recovered up to 99% and 81.7% of the normal control levels, respectively (P < 0.05), and cellular survival improved (P < 0.01).Our results demonstrate that overexpression of the β2AR gene in cardiomyocytes exposed to chronic hypoxia provides significant catecholamine-dependent inotropic support and cellular protection.

Research highlights
► Chronic hypoxia results in β2AR malfunction of the cardiomyocytes.
► β2AR overexpression in cardiomyocytes under chronic hypoxia enhances contractility.
► β2AR overexpression in cardiomyocytes under chronic hypoxia improves cell survival.