Muriel G Blin1, Richard Bachelier1, Karim Fallague1, Karima Moussouni1, Michel Aurrand-Lions2, Samantha Fernandez3, Benjamin Guillet4, Stéphane Robert1, Alexandrine Foucault-Bertaud1, Nathalie Bardin5, Marcel Blot-Chabaud1, Françoise Dignat-George5, Aurélie S Leroyer6. 1. Aix-Marseille Univ., INSERM 1263, INRA 1260, C2VN, Marseille, France. 2. Aix Marseille Univ., CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. 3. Aix-Marseille Univ., CERIMED, Secteur Nucléaire Pré-clinique, Timone, 13005 Marseille, France. 4. Aix-Marseille Univ., INSERM 1263, INRA 1260, C2VN, Marseille, France; Aix-Marseille Univ., CERIMED, Secteur Nucléaire Pré-clinique, Timone, 13005 Marseille, France; Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Marseille, France. 5. Aix-Marseille Univ., INSERM 1263, INRA 1260, C2VN, Marseille, France; Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, 13385 Marseille, France. 6. Aix-Marseille Univ., INSERM 1263, INRA 1260, C2VN, Marseille, France. Electronic address: aurelie.leroyer@univ-amu.fr.
Abstract
AIMS: The progression of atherosclerosis is based on the continued recruitment of leukocytes in the vessel wall. The previously described role of CD146 in leukocyte infiltration suggests an involvement for this adhesion molecule in the inflammatory response. In this study, we investigated the role of CD146 in leukocyte recruitment by using an experimental model of atherogenesis. METHODS AND RESULTS: The role of CD146 was explored in atherosclerosis by crossing CD146-/- mice with ApoE-/- mice. CD146 -/-/ApoE -/- and ApoE -/- mice were fed a Western diet for 24 weeks and were monitored for aortic wall thickness using high frequency ultrasound. The arterial wall was significantly thicker in CD146-deficient mice. After 24 weeks of Western diet, a significant increase of atheroma in both total aortic lesion and aortic sinus of CD146-null mice was observed. In addition, atherosclerotic lesions were more inflammatory since plaques from CD146-deficient mice contained more neutrophils and macrophages. This was due to up-regulation of RANTES secretion by macrophages in CD146-deficient atherosclerotic arteries. This prompted us to further address the function of CD146 in leukocyte recruitment during acute inflammation by using a second experimental model of peritonitis induced by thioglycollate. Neutrophil recruitment was significantly increased in CD146-deficient mice 12 h after peritonitis induction and associated with higher RANTES levels in the peritoneal cavity. In CD146-null macrophages, we also showed that increased RANTES production was dependent on constitutive inhibition of the p38-MAPK signaling pathway. Finally, Maraviroc, a RANTES receptor antagonist, was able to reduce atherosclerotic lesions and neutrophilia in CD146-deficient mice to the same level as that found in ApoE -/- mice. CONCLUSIONS: Our data indicate that CD146 deficiency is associated with the upregulation of RANTES production and increased inflammation of atheroma, which could influence the atherosclerotic plaque fate. Thus, these data identify CD146 agonists as potential new therapeutic candidates for atherosclerosis treatment.
AIMS: The progression of atherosclerosis is based on the continued recruitment of leukocytes in the vessel wall. The previously described role of CD146 in leukocyte infiltration suggests an involvement for this adhesion molecule in the inflammatory response. In this study, we investigated the role of CD146 in leukocyte recruitment by using an experimental model of atherogenesis. METHODS AND RESULTS: The role of CD146 was explored in atherosclerosis by crossing CD146-/- mice with ApoE-/- mice. CD146 -/-/ApoE -/- and ApoE -/- mice were fed a Western diet for 24 weeks and were monitored for aortic wall thickness using high frequency ultrasound. The arterial wall was significantly thicker in CD146-deficientmice. After 24 weeks of Western diet, a significant increase of atheroma in both total aortic lesion and aortic sinus of CD146-null mice was observed. In addition, atherosclerotic lesions were more inflammatory since plaques from CD146-deficientmice contained more neutrophils and macrophages. This was due to up-regulation of RANTES secretion by macrophages in CD146-deficient atherosclerotic arteries. This prompted us to further address the function of CD146 in leukocyte recruitment during acute inflammation by using a second experimental model of peritonitis induced by thioglycollate. Neutrophil recruitment was significantly increased in CD146-deficientmice 12 h after peritonitis induction and associated with higher RANTES levels in the peritoneal cavity. In CD146-null macrophages, we also showed that increased RANTES production was dependent on constitutive inhibition of the p38-MAPK signaling pathway. Finally, Maraviroc, a RANTES receptor antagonist, was able to reduce atherosclerotic lesions and neutrophilia in CD146-deficientmice to the same level as that found in ApoE -/- mice. CONCLUSIONS: Our data indicate that CD146 deficiency is associated with the upregulation of RANTES production and increased inflammation of atheroma, which could influence the atherosclerotic plaque fate. Thus, these data identify CD146 agonists as potential new therapeutic candidates for atherosclerosis treatment.
Authors: Alexander Balatskiy; Ilia Ozhimalov; Maria Balatskaya; Alexandra Savina; Julia Filatova; Natalia Kalinina; Vladimir Popov; Vsevolod Tkachuk Journal: Int J Mol Sci Date: 2022-02-03 Impact factor: 5.923
Authors: Bryce R Evans; Anaïs Yerly; Emiel P C van der Vorst; Iris Baumgartner; Sarah Maike Bernhard; Marc Schindewolf; Yvonne Döring Journal: Front Cardiovasc Med Date: 2022-05-04