Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis

Autor: Carbone, Maria Luigia, Chadeuf, Gilliane, Heurtebise-Chrétien, Sandrine, Prieur, Xavier, Quillard, Thibault, Goueffic, Yann, Vaillant, Nathalie, Rio, Marc, Castan, Laure, Durand, Maxim, Baron-Menguy, Céline, Aureille, Julien, Desfrançois, Juliette, Tesse, Angela, Torres, Raul M., Loirand, Gervaise
Přispěvatelé: unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Plateforme CYTOCELL Nantes (CRCINA-CYTOCELL), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Rok vydání: 2017
Předmět:
Zdroj: Journal of Clinical Investigation
Journal of Clinical Investigation, American Society for Clinical Investigation, 2017, Equipe III Equipe IV, 127 (12), pp.4516--4526. ⟨10.1172/JCI92702⟩
ISSN: 1558-8238
0021-9738
DOI: 10.1172/JCI92702⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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