GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis

Yu, Haojie; Rimbert, Antoine; Palmer, Alice E.; Toyohara, Takafumi; Xia, Yulei; Xia, Fang; Ferreira, Leonardo M. R.; Chen, Zhifen; Chen, Tao; Loaiza, Natalia; Horwitz, Nathaniel Brooks; Kacergis, Michael C.; Zhao, Liping; Soukas, Alexander A.; Kuivenhoven, Jan Albert; Kathiresan, Sekar; Cowan, Chad A.

doi:10.1016/j.cell.2019.10.034

Cited by 69 publications

(65 citation statements)

References 45 publications

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“…ERK1/2 inhibition also activates macrophage ABCG1 expression to inhibit macrophage/foam cell formation 29 . Our findings of anti-atherogenic properties of ERK1/2 inhibition have been confirmed by a recent report, which demonstrates protection against hypercholesterolemia and atherosclerosis by deficiency of orphan G protein-coupled receptor 146 (GPR146) expression is tightly linked to reduced ERK1/2 activity 30 . In spite of above findings, the detailed anti-atherogenic actions and the underlying mechanisms by ERK1/2 inhibition, particularly the effect and detailed mechanisms on vascular calcification and the interactions between ECs and SMCs, need more investigation.…”

Section: Introductionsupporting

confidence: 86%

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway

et al. 2021

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Rationale : Vascular microcalcification increases the risk of rupture of vulnerable atherosclerotic lesions. Inhibition of ERK1/2 reduces atherosclerosis in animal models while its role in vascular calcification and the underlying mechanisms remains incompletely understood. Methods: Levels of activated ERK1/2, DKK1, LRP6 and BMP2 in human calcific aortic valves were determined. ApoE deficient mice received ERK1/2 inhibitor (U0126) treatment, followed by determination of atherosclerosis, calcification and miR-126-3p production. C57BL/6J mice were used to determine the effect of U0126 on Vitamin D 3 (VD 3 )-induced medial arterial calcification. HUVECs, HAECs and HASMCs were used to determine the effects of ERK1/2 inhibitor or siRNA on SMC calcification and the involved mechanisms. Results : We observed the calcification in human aortic valves was positively correlated to ERK1/2 activity. At cellular and animal levels, U0126 reduced intimal calcification in atherosclerotic lesions of high-fat diet-fed apoE deficient mice, medial arterial calcification in VD 3 -treated C57BL/6J mice, and calcification in cultured SMCs and arterial rings. The reduction of calcification was attributed to ERK1/2 inhibition-reduced expression of ALP, BMP2 and RUNX2 by activating DKK1 and LRP6 expression, and consequently inactivating both canonical and non-canonical Wnt signaling pathways in SMCs. Furthermore, we determined ERK1/2 inhibition activated miR-126-3p production by facilitating its maturation through activation of AMPKα-mediated p53 phosphorylation, and the activated miR-126-3p from ECs and SMCs played a key role in anti-vascular calcification actions of ERK1/2 inhibition. Conclusions : Our study demonstrates that activation of miR-126-3p production in ECs/SMCs and interactions between ECs and SMCs play an important role in reduction of vascular calcification by ERK1/2 inhibition.

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Section: Introductionsupporting

confidence: 86%

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway

et al. 2021

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“…Moreover, the cancer genome database showed that higher expression levels of GPR146 in patients with breast cancer. These findings further support the results of current study [43][44][45].…”

Section: Plos Onesupporting

confidence: 93%

Associations of serum C-peptide and insulin-like growth factor binding proteins-3 with breast cancer deaths

et al. 2020

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C-peptide is usually considered as a marker of insulin secretion and has no physiological function. This study aimed to assess the association between serum C-peptide level as independent risk factor and breast cancer and explored the possible underlying mechanisms. This was a population-based cohort study. All the data was collected according to a standard protocol. The C-peptide and insulin-like growth factor binding proteins-3(IGFBP-3) concentrations were measured in blood. The breast cancer deaths were confirmed by National Death Index records. Cox proportional hazard regression analysis was conducted to determine the hazard ratio of serum C-peptide level for breast cancer deaths. Analysis of covariance was used to assess the association between serum C-peptide and IGFBP-3 level, and the linear trend was tested by using a linear model. A total of 8,373 women 17 years of age or older were included in the study, and 57 breast cancer deaths were observed over the study period. The result of survival analysis showed that breast cancer deaths increased with increasing levels of serum C-peptide. The hazard ratio was 1.69 (95% confidence interval, 1.17–2.45). The levels of circulating IGFBP-3 were positively associated with changes in serum C-peptide levels and showed a strong linear trend in the covariance analysis. Serum C-peptide level was associated with increased risk of breast cancer death. Our results suggest that the increased risk of breast cancer death can be via a pathway that serum C-peptide level positive associated with the change in serum IGFBP-3 level.

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“…GPR146 (37 kDa), an orphan G protein-coupled receptor, has been proposed as a C-peptide receptor. Most recently, Yu et al (2019) showed that GPR146 regulates plasma cholesterol levels via ERK signaling and that GPR146 knockout mice are viable and fertile. Heat shock protein HSPB8 also known as HSP22 (22 kDa) is a cytoplasmic protein that serves as a member of the chaperone-assisted autophagy complex and is involved in Charcot-Marie-Tooth disease type 2L as well as in a rare form of human distal myopathy (Ghaoui et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

RNA‐Seq identifies genes whose proteins are upregulated during syncytia development in murine C2C12 myoblasts and human BeWo trophoblasts

et al. 2021

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GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis

Cited by 69 publications

References 45 publications

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway

Associations of serum C-peptide and insulin-like growth factor binding proteins-3 with breast cancer deaths

RNA‐Seq identifies genes whose proteins are upregulated during syncytia development in murine C2C12 myoblasts and human BeWo trophoblasts

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