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Resolvin E1/ChemR23 Protects Against Hypertension and Vascular Remodeling in Angiotensin II-Induced Hypertensive Mice.

Abstract

BACKGROUND

Inflammation plays a critical role in the development of hypertension and vascular remodeling. Resolvin E1 (RvE1), as one of the specialized proresolving lipid mediators, promotes inflammation resolution by binding with a G protein-coupled receptor, ChemR23 (chemerin receptor 23). However, whether RvE1/ChemR23 regulates hypertension and vascular remodeling is unknown.

METHODS

Hypertension in mice was induced by Ang II (angiotensin II) infusion (750 ng/kg per minute), and RvE1 (2 microg/kg per day) was administered through intraperitoneal injection. Loss of ChemR23 was achieved by mice receiving intravenous injection of adeno-associated virus 9-encoding shRNA against ChemR23.

RESULTS

Aortic ChemR23 expression was increased in Ang II- induced hypertensive mice and that ChemR23 was mainly expressed on vascular smooth muscle cells (VSMCs). RvE1 lowered blood pressure, reduced aortic media thickness, attenuated aortic fibrosis, and mitigated VSMC phenotypic transformation and proliferation in hypertensive mice, which were all reversed by the knockdown of ChemR23. Moreover, RvE1 reduced the aortic infiltration of macrophages and T cells, which was also reversed by ChemR23 knockdown. RvE1 inhibited Ccl5 expression in VSMCs via the AMPKalpha (AMP-activated protein kinase alpha)/Nrf2 (nuclear factor E2-related factor 2)/canonical NF-kappaB (nuclear factor kappaB) pathway, thereby reducing the infiltration of macrophages and T cells. The AMPKalpha/Nrf2 pathway also mediated the effects of RvE1 on VSMC phenotypic transformation and proliferation. In patients with hypertension, the serum levels of RvE1 and other eicosapentaenoic acid- derived metabolites were significantly decreased.

CONCLUSIONS

RvE1/ChemR23 ameliorated hypertension and vascular remodeling by activating AMPKalpha/Nrf2 signaling, which mediated immune cell infiltration by inhibiting the canonical NF-kappaB/Ccl5 pathway, and regulated VSMC proliferation and phenotypic transformation. RvE1/ChemR23 may be a potential therapeutic target for hypertension.

Authors

Zhang, Jishou,Yin, Zheng,Xu, Yao,Wei, Cheng,Peng, Shanshan,Zhao, Mengmeng,Liu, Jianfang,Xu, Shuwan,Pan, Wei,Zheng, Zihui,Liu, Siqi,Ye, Jing,Qin, Juan-Juan,Wan, Jun,Wang, Menglong
Published Date 2023 Dec