Angiotensin II Activates NF-?B Through AT1A Receptor Recruitment of ?-arrestin in Cultured Rat Vascular Smooth Muscle Cells.

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Angiotensin II Activates NF-?B Through AT1A Receptor Recruitment of ?-arrestin in Cultured Rat Vascular Smooth Muscle Cells.

Am J Physiol Cell Physiol. 2013 Apr 10;

Authors: Morinelli TA, Lee MH, Kendall RT, Luttrell L, Walker LP, Ullian ME

Abstract
Activation of the angiotensin II (AngII) AT1A receptor (AT1AR) in rat aorta vascular smooth muscle cells (RASMC) results in the increased synthesis of the pro-inflammatory enzyme cyclooxygenase 2 (COX-2). We have previously shown that nuclear localization of internalized AT1AR results in activation of transcription of the gene for COX-2, PTGS-2. Others have suggested that AngII stimulation of COX-2 protein synthesis is mediated by NF-?B. The purpose of the present study was to examine the interrelationship between AT1AR activation, ?-arrestin recruitment and NF-?B activation in the ability of AngII to increase COX-2 protein synthesis in RASMC. In the present study we utilized RASMC, inhibitors of the NF-?B pathway, ?-arrestin knock down, radioligand binding, immunoblotting and immunofluorescence to characterize the roles of AT1AR internalization, NF-?B activation and ?-arrestin in AngII-induced COX-2 synthesis. Ro 106-9920 or parthenolide, agents that inhibit the initial steps of NF-?B activation, blocked AngII-induced p65 NF-?B nuclear localization, COX-2 protein expression, ?-arrestin recruitment, and AT1AR internalization, without inhibiting AngII-induced p42/44 ERK activation. Curcumin, an inhibitor of NF-?B induced transcription, blocked AngII-induced COX-2 protein expression without altering AT1AR internalization, AngII-induced p65 NF-?B nuclear localization or p42/44 ERK activation. SiRNA-induced knockdown of ?-arrestin 1 and 2 inhibited AngII-induced p65 NF-?B nuclear localization. In vascular smooth muscle cells, internalization of the activated AT1AR mediated by ?-arrestins activates the NF-?B pathway, producing nuclear localization of the transcription factor and initiation of COX-2 protein synthesis; thereby linking the internalization of the receptor with the NF-?B pathway.

PMID: 23576578 [PubMed - as supplied by publisher]

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