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The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism.

ABSTRACT: The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from Ldlr ^-/- rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.

SUBMITTER: Cui X

PROVIDER: S-EPMC8351205 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism.

Cui Xueqin X Xing Roumei R Tian Yue Y Wang Man M Sun Yue Y Xu Yongqian Y Yang Yiqing Y Zhao Yongliang Y Xie Ling L Xiao Yufang Y Li Dali D Zheng Biao B Liu Mingyao M Chen Huaqing H

Frontiers in physiology 20210726

The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from <i>Ldlr</i> <sup>-/-</sup> rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid dis ...[more]

PMID: 34381373

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Project description:ObjectiveC1q/TNF-related proteins 1 (CTRP1) is a recently identified adiponectin associated with obesity-linked disorders and adverse cardiovascular events. The effect of CTRP1 on cardiac fibrosis has not yet been fully elucidated; thus, we aimed to explore this association.Materials and methodsIn this experimental study, a mouse model of cardiac fibrosis was established by administering isoproterenol (ISO) (subcutaneously injecting 10 mg/kg/day for 3 days and then 5 mg/kg/day for 11 days). Mice were also injected with recombinant CTRP1 protein (200 μg/kg) 14 days after the final ISO administration. Adult mouse fibroblasts were isolated and stimulated with transforming growth factor (TGF) β1, followed by treatment with recombinant CTRP1. Primary bone marrow-derived macrophages were isolated from C57BL/6J mice and treated with recombinant CTRP1 as well.ResultsCTRP1 level was increased in mouse plasma and heart tissue 2 weeks after ISO injection. Our findings indicated that recombinant CTRP1 injection aggravated ISO-induced cardiac fibrosis and dysfunction. However, recombinant CTRP1 did not alter TGFβ1-induced fibroblast proliferation and activation or collagen transcription. Recombinant CTRP1 exacerbated ISO-induced macrophage infiltration and inflammatory response. We determined that macrophages treated with recombinant CTRP1 showed increased pro-inflammatory cytokine release. Fibroblasts co-cultured with macrophages treated with recombinant CTRP1 showed increased proliferation and collagen transcription. We also found that CTRP1 upregulated the NADPH oxidase 2 (NOX2)/p38 pathway in macrophages. When we inhibited p38 signaling, the pro-inflammatory effect of CTRP1 on macrophages was counteracted. Fibroblasts co-cultured with macrophages treated with a p38 inhibitor also showed limited proliferation and collagen transcription.ConclusionCardiac fibrosis was aggravated with the activation of the NOX2/p38 pathway in macrophages after CTRP1 treatment.

Dataset Information

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism.

Publications

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism.

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