Vascular hyporesponsiveness in sepsis is associated with nitric oxide-dependent activation of G-protein receptor kinase 2

Abstract

Sepsis is a life-threatening condition caused by a dysregulated host response to infection that often leads to profound end organ derangement in which vascular system dysfunction plays a critical role. Septic shock is characterized by a pronounced decrease in peripheral vascular resistance, progressive hypotension, and lack of response to vasoconstrictors. We have previously shown that sepsis induced cardiac hyporesponsiveness to isoproterenol by a nitric oxide (NO)-dependent mechanism, mediated by increased G-protein receptor kinase 2 (GRK2) expression and receptor phosphorylation. In the present report, we investigated whether this mechanism is relevant in the vascular system. The contractile response of aortic rings and the in vivo responsiveness to phenylephrine were significantly reduced in septic mice at both 12 and 24 hours after cecal ligation and puncture surgery. Higher expression of GRK2 and increased phosphorylated GRK2 were detected in the aorta of septic mice along with a reduction in the density of alpha-1 adrenergic receptors. Treatment with the selective NOS-2 inhibitor 1400 W prevented vessel hyporesponsiveness, abolished GRK2 expression and activation and preserved alpha-1 adrenergic receptor density. Naïve mouse aorta rings incubated with a NO donor displayed diminished contractile response, and this effect was prevented by a GRK2 inhibitor. Our study showed that during sepsis, NOS-2-derived NO induces and activates GRK2, leading to alpha-1 adrenergic receptor internalization and hyporesponsiveness to vasoconstrictors. Therefore, our findings suggest that GRK2 inhibition is a potential new therapeutic target in sepsis-induced vascular dysfunction.