Cardiovascular Research Advance Access first published online on October 20, 2009
This version [Corrected Proof] published online on November 21, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp347
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β2 integrins modulate the initiation and progression of atherosclerosis in low-density lipoprotein receptor knockout mice
1 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, R630, Houston, TX 77030, USA
2 INSERM 828, Avenue Haut Leveque, Pessac, France
3 Department of Molecular and Cellular Biology and Medicine, Division of Diabetes, Endocrinology & Metabolism, St Luke's Episcopal Hospital, Houston, TX 77030, USA
* Corresponding author. Tel: +1 713 798 4999, Fax: +1 713 798 8764, Email: amerched{at}bcm.edu
Aims: β2 integrin-mediated adhesion is thought to be a key event in cardiovascular disease. However, results of clinical trials targeting these molecules have been disappointing. Here, we investigated the effect of inactivation of β2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18–/– cells in low-density lipoprotein receptor knockout (LDLR–/–) mice.
Methods and results: Early BMT before fatty streak formation revealed a short-term protective effect of CD18 (34% atherosclerotic lesion reduction). Once fatty streak lesions had developed (5-week atherogenic diet) before BMT, β2 integrin expression did not affect lesion progression. However, after the establishment of more mature lesions (pre-feeding mice the atherogenic diet for 10 weeks), CD18+/+ BMT enhanced atherosclerosis (36%) lesion progression compared with CD18–/– BMT. Furthermore, β2 integrins modulated the capacity of isolated peritoneal macrophages to take up acetylated LDL and native LDL and to phagocytose apoptotic cells, possibly via CD18-dependent mitogen-activated protein kinase signalling. Gene expression profile of CD18–/– and CD18+/+ macrophages revealed significant differences in putative protective as well as atherogenic functions.
Conclusion: β2 integrin-mediated interaction between leucocytes and the vessel wall is a time-dependent and dynamic process. During the initiation phase, it protects against atherosclerotic lesion formation. However, with the evolution of the lesion and chronic exposure to dyslipidaemia, β2 integrins’ pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.
KEYWORDS Atherosclerosis; Adhesion; Integrins; Inflammation; Mice
Time for primary review: 30 days