beta 3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-05, Vol.100 (11), p.6730-6735
• Main Authors: Weng, S, Zemany, L, Standley, K N, Novack, D V, Regina, M L, Bernal-Mizrachi, C, Coleman, T, Semenkovich, C F
• Format: Article
• Language: English
• ISSN: 0027-8424
• DOI: 10.1073/pnas.1137612100

Hyperlipidemia promotes the chronic inflammatory disease atherosclerosis through poorly understood mechanisms. Atherogenic lipoproteins activate platelets, but it is unknown whether platelets contribute to early inflammatory atherosclerotic lesions. To address the role of platelet aggregation in diet- induced vascular disease, we studied beta 3 integrin-deficient mice (lacking platelet integrin alpha IIb beta 3 and the widely expressed nonplatelet integrin alpha v beta 3) in two models of atherosclerosis, apolipoprotein E (apoE)-null and low-density lipoprotein receptor (LDLR)-null mice. Unexpectedly, a high-fat, Western-type (but not a low-fat) diet caused death in two-thirds of the beta 3 super(-) super(/) super(-)apoE super(-) super(/) super(-) and half of the beta 3 super(- ) super(/) super(-)LDLR super(-) super(/) super(-) mice due to noninfectious pneumonitis. In animals from both models surviving high-fat feeding, pneumonitis was absent, but aortic atherosclerosis was 2- to 6-fold greater in beta 3 super(-) super(/) super(-) compared with beta super(+) super(/) super(+) littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of beta 3 super(-) super(/) super(-)LDLR super(-) super(/) super(-) mice. Each was also increased in smooth muscle cells cultured from beta 3-deficient mice and suppressed by retroviral reconstitution of beta 3. These data show that the platelet defect caused by alpha IIb beta 3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that alpha v beta 3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.