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 β3 integrin-deficient mice (lacking platelet integrin αIIbβ3 and the widely expressed nonplatelet integrin αvβ3) 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 β3-/--apoE-/- and half of the β3-/-LDLR-/- 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 β3-/- compared with β+/+ littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of β3-/- LDLR-/- mice. Each was also increased in smooth muscle cells cultured from β3-deficient mice and suppressed by retroviral reconstitution of β3. These data show that the platelet defect caused by αIIbβ3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that αvβ3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - May 27 2003|