Overexpression of ß-Arrestin1 in the Rostral Ventrolateral Medulla Downregulates Angiotensin Receptor and Lowers Blood Pressure in Hypertension.
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ABSTRACT: Background: Hypertension is characterized by sympathetic overactivity, which is associated with an enhancement in angiotensin receptor type I (AT1R) in the rostral ventrolateral medulla (RVLM). ?-arrestin1, a canonical scaffold protein, has been suggested to show a negative effect on G protein-coupled receptors via its internalization and desensitization and/or the biased signaling pathway. The major objectives of the present study were to observe the effect of ?-arrestin1 overexpression in the RVLM on cardiovascular regulation in spontaneously hypertensive rats (SHR), and further determine the effect of ?-arrestin1 on AT1R expression in the RVLM. Methods: The animal model of ?-arrestin1 overexpression was induced by bilateral injection of adeno-associated virus containing Arrb1 gene (AAV-Arrb1) into the RVLM of WKY and SHR. Results: ?-arrestin1 was expressed on the pre-sympathetic neurons in the RVLM, and its expression in the RVLM was significantly (P < 0.05) downregulated by an average of 64% in SHR than WKY. Overexpression of ?-arrestin1 in SHR significantly decreased baseline levels of blood pressure and renal sympathetic nerve activity, and attenuated cardiovascular effects induced by RVLM injection of angiotensin II (100 pmol). Furthermore, ?-arrestin1 overexpression in the RVLM significantly reduced the expression of AT1R by 65% and NF-?B p65 phosphorylation by 66% in SHR. It was confirmed that ?-arrestin1 overexpression in the RVLM led to an enhancement of interaction between ?-arrestin1 and I?B-?. Conclusion: Overexpression of ?-arrestin1 in the RVLM reduces BP and sympathetic outflow in hypertension, which may be associated with NF?B-mediated AT1R downregulation.
SUBMITTER: Sun JC
PROVIDER: S-EPMC5882868 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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