Increased expression of chemerin in endothelial cells due to Fli1 deficiency may contribute to the development of digital ulcers in systemic sclerosis

Akamata, Kaname; Asano, Yoshihide; Taniguchi, Takashi; Yamashita, Takashi; Saigusa, Ryosuke; Nakamura, Kouki; Noda, Shinichi; Aozasa, Naohiko; Toyama, Tetsuo; Takahashi, Takehiro; Ichimura, Yohei; Sumida, Hitoshi; Tada, Yayoi; Sugaya, Makoto; Kadono, Takafumi; Sato, Shinichi

doi:10.1093/rheumatology/keu479

Cited by 40 publications

(50 citation statements)

References 36 publications

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“…Chemerin mRNA and protein localized to the endothelium, smooth muscle, and fat cells of human vessels, placing it in close proximity to its receptors, suggesting that it could act as a locally released mediator and levels could be elevated in pathologies, such as obesity and metabolic syndrome. This staining is consistent with other literature, which found that chemerin was expressed in dermal microvascular endothelial cells 34 and the smooth muscle medial layer of arteries. 33 Interestingly, expression in smooth muscle is similar to another adipokine, adiponetin.…”

Section: Chemerin and Chemerin Receptors Are Widely Expressed In The supporting

confidence: 93%

Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

Kennedy

Yang

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et al. 2016

JAHA

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BackgroundCirculating levels of chemerin are significantly higher in hypertensive patients and positively correlate with blood pressure. Chemerin activates chemokine‐like receptor 1 (CMKLR1 or ChemR23) and is proposed to activate the “orphan” G‐protein‐coupled receptor 1 (GPR1), which has been linked with hypertension. Our aim was to localize chemerin, CMKLR1, and GPR1 in the human vasculature and determine whether 1 or both of these receptors mediate vasoconstriction.Methods and ResultsUsing immunohistochemistry and molecular biology in conduit arteries and veins and resistance vessels, we localized chemerin to endothelium, smooth muscle, and adventitia and found that CMKLR1 and GPR1 were widely expressed in smooth muscle. C9 (chemerin149–157) contracted human saphenous vein (pD 2=7.30±0.31) and resistance arteries (pD 2=7.05±0.54) and increased blood pressure in rats by 9.1±1.0 mm Hg at 200 nmol. Crucially, these in vitro and in vivo vascular actions were blocked by CCX832, which we confirmed to be highly selective for CMKLR1 over GPR1. C9 inhibited cAMP accumulation in human aortic smooth muscle cells and preconstricted rat aorta, consistent with the observed vasoconstrictor action. Downstream signaling was explored further and, compared to chemerin, C9 showed a bias factor=≈5000 for the Gi protein pathway, suggesting that CMKLR1 exhibits biased agonism.ConclusionsOur data suggest that chemerin acts at CMKLR1, but not GPR1, to increase blood pressure. Chemerin has an established detrimental role in metabolic syndrome, and these direct vascular actions may contribute to hypertension, an additional risk factor for cardiovascular disease. This study provides proof of principle for the therapeutic potential of selective CMKLR1 antagonists.

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Section: Chemerin and Chemerin Receptors Are Widely Expressed In The supporting

confidence: 93%

Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

Kennedy

Yang

Read

et al. 2016

JAHA

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“…For instance, neuropilin-1 is decreased both in HDMECs from patients with SSc and in HDMECs transfected with FLI1 siRNA, and the transient knockdown of neuropilin-1 causes impaired tube formation of HDMECs. [42] Chemerin, the expression of which is elevated in endothelial cells of Fli1 +/− mice as well as HDMECs transfected with FLI1 siRNA, [43] also promotes the proliferation of human endothelial cells. [40] These findings are compatible with the result of this study showing that Fli1 deficiency leads to the impaired tube formation of HDMECs.…”

Section: Discussionmentioning

confidence: 99%

The impact of transcription factor Fli1 deficiency on the regulation of angiogenesis

Toyama

Asano

Miyagawa

et al. 2017

Experimental Dermatology

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The insufficiency of Friend leukaemia virus integration 1 (Fli1), a member of the Ets family transcription factors, is implicated in the pathogenesis of vasculopathy associated with systemic sclerosis (SSc). Fli1 deficiency accelerates early steps of angiogenesis, including detachment of pre-existing pericytes and extracellular matrix degradation by endothelial proteinases, but the impact of Fli1 deficiency on the other steps of angiogenesis has not been investigated. Therefore, we evaluated the effect of Fli1 deficiency on migration, proliferation, cell survival and tube formation of human dermal microvascular endothelial cells (HDMECs). HDMECs transfected with FLI1 siRNA exhibited a greater migratory property in scratch assay and transwell migration assay and a higher proliferation rate in BrdU assay than HDMECs transfected with non-silencing scrambled RNA. In flow cytometry-based apoptosis assay, FLI1 siRNA-transduced HDMECs revealed the decreased number of annexin and propidium iodide-double-positive apoptotic cells compared with control cells, reflecting the promotion of cell survival. On the other hand, tubulogenic activity on Matrigel was remarkably suppressed in Fli1-deficient HDMECs relative to control cells. These results indicate that Fli1 deficiency promotes migration, proliferation and cell survival, while abating tube formation of endothelial cells, suggesting that Fli1 deficiency is potentially attributable to the development of both proliferative obliterative vasculopathy (occlusion of arterioles and small arteries) and destructive vasculopathy (loss of small vessels) characteristic of SSc vasculopathy.

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“…As BLM‐treated mice show the fibrotic and inflammatory aspects of SSc, but not its vascular aspect, we next focused our interest on endothelial cells. To this end, we investigated the association of the transcription factor Fli1 with LL‐37 and CRAMP expression in endothelial cells, because Fli1 has been shown to be a potential predisposing factor of SSc, whose deficiency is largely associated with the induction of an SSc‐like vascular phenotype in vivo and in vitro . Consistently with this notion, gene silencing of Fli1 resulted in the induction of CAMP mRNA expression in HDMECs (Fig.…”

Section: Resultsmentioning

confidence: 56%

A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis

et al. 2016

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Increased expression of chemerin in endothelial cells due to Fli1 deficiency may contribute to the development of digital ulcers in systemic sclerosis

Abstract: Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-β, while it is up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. Increased chemerin expression in dermal blood vessels may be associated with the development of digital ulcers in SSc.

Cited by 40 publications

References 36 publications

Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

Chemerin Elicits Potent Constrictor Actions via Chemokine‐Like Receptor 1 (CMKLR1), not G‐Protein‐Coupled Receptor 1 (GPR1), in Human and Rat Vasculature

The impact of transcription factor Fli1 deficiency on the regulation of angiogenesis

A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis

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