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Disturbed flow–induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis
Akiko Nakayama, … , Lee S. Weinstein, Stefan Offermanns
Akiko Nakayama, … , Lee S. Weinstein, Stefan Offermanns
Published December 3, 2020
Citation Information: JCI Insight. 2020;5(23):e140485. https://doi.org/10.1172/jci.insight.140485.
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Research Article Inflammation Vascular biology

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

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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.

Authors

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

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Figure 2

Endothelial inflammation induced by disturbed flow is suppressed by cAMP-PKA signaling in HUVECs.

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Endothelial inflammation induced by disturbed flow is suppressed by cAMP...
(A and B) Confluent HUVECs were transfected with control siRNA or siRNA directed against Gαs and were then exposed to oscillatory (osc.) flow for the indicated time periods. NF-κB (p65) phosphorylation, as well as CREB phosphorylation (A) or levels of IκBα (B), were determined by immunoblotting. The diagrams show the densitometric evaluation of immunoblots (n = 3 independent experiments). (C) Control or Gαs knockdown HUVECs were incubated without or with 50 μM db-cAMP for 30 minutes before induction of osc. flow (3 hours). Inflammatory gene expression was analyzed by qPCR (n = 4 independent experiments). (D) Confluent HUVECs were incubated without or with the PKA-inhibitor PKI (1 μM), followed by induction of osc. flow, and inflammatory gene expression (n = 4 independent experiments) was determined. Data represent mean values ± SD; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 (2-way ANOVA and Bonferroni’s post hoc test).

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