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Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis
Maria Luigia Carbone, … , Raul M. Torres, Gervaise Loirand
Maria Luigia Carbone, … , Raul M. Torres, Gervaise Loirand
Published November 13, 2017
Citation Information: J Clin Invest. 2017;127(12):4516-4526. https://doi.org/10.1172/JCI92702.
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Research Article Vascular biology

Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis

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Abstract

Abnormal activity of the renin-angiotensin-aldosterone system plays a causal role in the development of hypertension, atherosclerosis, and associated cardiovascular events such as myocardial infarction, stroke, and heart failure. As both a vasoconstrictor and a proinflammatory mediator, angiotensin II (Ang II) is considered a potential link between hypertension and atherosclerosis. However, a role for Ang II–induced inflammation in atherosclerosis has not been clearly established, and the molecular mechanisms and intracellular signaling pathways involved are not known. Here, we demonstrated that the RhoA GEF Arhgef1 is essential for Ang II–induced inflammation. Specifically, we showed that deletion of Arhgef1 in a murine model prevents Ang II–induced integrin activation in leukocytes, thereby preventing Ang II–induced recruitment of leukocytes to the endothelium. Mice lacking both LDL receptor (LDLR) and Arhgef1 were protected from high-fat diet–induced atherosclerosis. Moreover, reconstitution of Ldlr–/– mice with Arhgef1-deficient BM prevented high-fat diet–induced atherosclerosis, while reconstitution of Ldlr–/– Arhgef1–/– with WT BM exacerbated atherosclerotic lesion formation, supporting Arhgef1 activation in leukocytes as causal in the development of atherosclerosis. Thus, our data highlight the importance of Arhgef1 in cardiovascular disease and suggest targeting Arhgef1 as a potential therapeutic strategy against atherosclerosis.

Authors

Maria Luigia Carbone, Gilliane Chadeuf, Sandrine Heurtebise-Chrétien, Xavier Prieur, Thibault Quillard, Yann Goueffic, Nathalie Vaillant, Marc Rio, Laure Castan, Maxim Durand, Céline Baron-Menguy, Julien Aureille, Juliette Desfrançois, Angela Tesse, Raul M. Torres, Gervaise Loirand

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Figure 4

Deletion of Arhgef1 decreases immune cell accumulation and inflammation in atherosclerotic aorta.

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Deletion of Arhgef1 decreases immune cell accumulation and inflammation ...
(A) Representative photomicrographs of CD68 macrophage staining and corresponding quantitative analysis of macrophage accumulation in atherosclerotic lesions of Ldlr–/–Arhgef1lox/lox and Ldlr–/–Arhgef1–/– mice (original magnification, ×10; *P < 0.05, Mann-Whitney test). (B) Quantification of total leukocytes, T lymphocytes, and macrophages in atherosclerotic aorta of Ldlr–/–Arhgef1lox/lox and Ldlr–/–Arhgef1–/– by flow cytometry (*P < 0.05, **P < 0.01, Mann-Whitney test). (C) Measurements by quantitative reverse transcriptase PCR of mRNA levels of the macrophage markers Adgre1, Il1b, and Tnfa (encoding F4/80, IL-1β, and TNF-α, respectively) in atherosclerotic aorta of Ldlr–/–Arhgef1lox/lox and Ldlr–/–Arhgef1–/– (*P < 0.05, Mann-Whitney test). Results are expressed as relative quantity (RQ).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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