Background ADRB1 (
adrenergic receptor beta 1) responds to neuroendocrine stimulations, which have great implications in
hypertension. GRK2 (
G protein-coupled receptor kinase 2) is an essential regulator for many
G protein-coupled receptors and subsequent cell signaling cascades, but its role as a regulator of ADRB1 and associated
cardiac hypertrophy in
hypertension remains to be elucidated. Methods and Results In this study, we found the expressions of GRK2 and ADRB1 in peripheral blood mononuclear cells were positively associated with blood pressure levels in hypertensive patients and with their expression in heart. In vitro evidence showed a direct interaction in ADRB1 and GRK2 and genetic depletion of GRK2 blocks
epinephrine-induced upregulation of hypertrophic and fibrotic genes in cardiomyocytes. Meanwhile, we discovered a
selective serotonin reuptake inhibitor paroxetine specifically blockades GRK2 and ADRB1 interaction. In vivo,
paroxetine treatment ameliorates
hypertension-induced
cardiac hypertrophy, dysfunction, and
fibrosis in animal models. We found that
paroxetine suppressed sympathetic overdrive and increased the
adrenergic receptor sensitivity to
catecholamines.
Paroxetine treatment also blocks
epinephrine-induced upregulation of hypertrophic and fibrotic genes as well as ADRB1 internalization in cardiomyocytes. Coadministration of
paroxetine further potentiates
metoprolol-induced reductions in blood pressure and heart rate, further attenuating
cardiac hypertrophy in spontaneously hypertensive rats. Furthermore, in patients with
hypertension accompanied with depression, we observed that cardiac remodeling was less severe in those with
paroxetine treatment compared with those with other types of anti-depressive agents. Conclusions
Paroxetine promotes ADRB1 sensitivity and attenuates
cardiac hypertrophy partially via blocking GRK2-mediated ADRB1 activation and internalization in the context of
hypertension.