Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis

Akiko Nakayama; Julián Albarrán-Juárez; Guozheng Liang; Kenneth Anthony Roquid; András Iring; Sarah Tonack; Min Chen; Oliver J Müller; Lee S Weinstein; Stefan Offermanns

doi:10.1172/jci.insight.140485

Disturbed flow-induced G_s-mediated signaling protects against endothelial inflammation and atherosclerosis

Akiko Nakayama, Julián Albarrán-Juárez, Guozheng Liang, Kenneth Anthony Roquid, András Iring, Sarah Tonack, Min Chen, Oliver J Müller, Lee S Weinstein, Stefan Offermanns

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor-like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow-induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.

Originalsprog	Engelsk
Artikelnummer	e140485
Tidsskrift	JCI Insight
Vol/bind	5
Nummer	23
DOI	https://doi.org/10.1172/jci.insight.140485
Status	Udgivet - dec. 2020
Udgivet eksternt	Ja

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10.1172/jci.insight.140485Licens: CC BY

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Citationsformater

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title = "Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis",

abstract = "Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor-like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow-induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.",

author = "Akiko Nakayama and Juli{\'a}n Albarr{\'a}n-Ju{\'a}rez and Guozheng Liang and Roquid, {Kenneth Anthony} and Andr{\'a}s Iring and Sarah Tonack and Min Chen and M{\"u}ller, {Oliver J} and Weinstein, {Lee S} and Stefan Offermanns",

year = "2020",

month = dec,

doi = "10.1172/jci.insight.140485",

language = "English",

volume = "5",

journal = "JCI Insight",

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publisher = "American Society for Clinical Investigation",

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T1 - Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis

AU - Nakayama, Akiko

AU - Albarrán-Juárez, Julián

AU - Liang, Guozheng

AU - Roquid, Kenneth Anthony

AU - Iring, András

AU - Tonack, Sarah

AU - Chen, Min

AU - Müller, Oliver J

AU - Weinstein, Lee S

AU - Offermanns, Stefan

PY - 2020/12

Y1 - 2020/12

N2 - Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor-like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow-induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.

AB - Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor-like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow-induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis.

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DO - 10.1172/jci.insight.140485

M3 - Journal article

C2 - 33268595

SN - 2379-3708

VL - 5

JO - JCI Insight

JF - JCI Insight

IS - 23

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