Beta3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice.
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 beta3 integrin-deficient mice (lacking platelet integrin alphaIIbbeta3 and the widely expressed nonplatelet integrin alphavbeta3) 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 beta3-/-apoE-/- and half of the beta3-/-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 beta3-/- compared with beta+/+ littermates. Expression of CD36, CD40L, and CD40 was increased in lungs of beta3-/-LDLR-/- mice. Each was also increased in smooth muscle cells cultured from beta3-deficient mice and suppressed by retroviral reconstitution of beta3. These data show that the platelet defect caused by alphaIIbbeta3 deficiency does not impair atherosclerotic lesion initiation. They also suggest that alphavbeta3 has a suppressive effect on inflammation, the loss of which induces atherogenic mediators that are amplified by diet-induced hyperlipidemia.
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sherry
S
Weng
Laura
L
Zemany
Kara N
KN
Standley
Deborah V
DV
Novack
Marie
M
La Regina
Carlos
C
Bernal-Mizrachi
Trey
T
Coleman
Clay F
CF
Semenkovich
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001161:Arteriosclerosis / Q000503:physiopathology*; D001483:Base Sequence; D017931:DNA Primers; D004041:Dietary Fats / Q000008:administration & dosage*; D006949:Hyperlipidemias / Q000503:physiopathology*; D039661:Integrin beta3 / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology; D011014:Pneumonia / Q000503:physiopathology*; D011973:Receptors, LDL / Q000235:genetics
D015703:Antigens, CD; D017931:DNA Primers; D004041:Dietary Fats; D039661:Integrin beta3; D011973:Receptors, LDL