title: Under-expression of α8 integrin aggravates experimental atherosclerosis.
abstract: Integrins play an important role in vascular biology. The α8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of α8 integrin to atherosclerosis and vascular remodelling. We hypothesized that α8 integrin expression is reduced in atherosclerotic lesions, and that its under-expression leads to a more severe course of atherosclerosis. α8 Integrin was detected by immunohistochemistry and qPCR and α8 integrin-deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross-sections. Second, after crossing into ApoE-deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: α8 integrin was detected in the media of human and murine vascular tissue and was down-regulated in arteries with advanced atherosclerotic lesions. In α8 integrin-deficient mice (α8(-/-) ) as well as α8(+/-) and α8(+/+) littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated α8(-/-) and α8(+/-) compared to ligated α8(+/+) animals. Carotid artery ligation increased smooth muscle cell number in the media of α8(+/+) mice and, more prominently, of α8(-/-) or α8(+/-) mice. On an ApoE(-/-) background, α8(+/-) and α8(-/-) mice developed more atherosclerotic plaques than α8(+/+) mice. α8 Integrin expression was reduced in α8(+/-) animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in α8(-/-) mice only. Thus, under-expression of α8 integrin aggravates vascular lesions, while a complete loss of α8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin α8β1 has a protective role in arterial remodelling and atherosclerosis.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Menendez-Castro
authors.forename: Nada
authors.initials: N
authors.lastname: Cordasic
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Ines
authors.initials: I
authors.lastname: Marek
authors.forename: Gudrun
authors.initials: G
authors.lastname: Volkert
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.forename: Angelika
authors.initials: A
authors.lastname: Jahn
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartner
mesh_terms: D000818:Animals; D001011:Aorta / Q000293:injuries / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D039001:Integrin alpha Chains / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology
chemical_list: D039001:Integrin alpha Chains; C093856:integrin alpha8
keywords: ApoE-deficient mice; atherosclerosis; carotid artery ligation; glomerulosclerosis; integrins; remodelling; α8 integrin-deficient mice