12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-kappaB.

نویسندگان

  • David T Bolick
  • Suseela Srinivasan
  • Angela Whetzel
  • Lauren C Fuller
  • Catherine C Hedrick
چکیده

OBJECTIVE 12/15 lipoxygenase (12/15LO) has been implicated as a mediator of inflammation and atherosclerosis. In the current study, we identified mechanisms through which 12/15LO mediates monocyte:endothelial interactions in vivo in apolipoprotein E-deficient mice (apoEKO), a well-characterized mouse model of atherosclerosis. METHODS AND RESULTS In apoEKO mice that are also deficient in 12/15LO (doubleKO), monocyte adhesion to aorta in vivo was reduced by 95% in doubleKO mice compared with apoEKO mice. Inhibition of 12/15LO in apoEKO mice in vivo using CDC (Cinnamyl-3,4-Dihydroxy-a-Cyanocinnamate) prevented monocyte adhesion to aortic endothelium in apoEKO mice. Aortic endothelium of apoEKO mice had significant activation of rhoA compared with doubleKO aortic endothelium. Further, apoEKO aorta displayed significant activation of NF-kappaB. DoubleKO aorta displayed little nuclear localization of NF-kappaB. Finally, we found significant upregulation of intercellular adhesion molecule-1 (ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKCalpha significantly reduced NF-kappaB activation, ICAM-1 induction, and monocyte adhesion to aorta. CONCLUSIONS We conclude that 12/15LO products activate endothelial rhoA and PKCalpha. Activation of rhoA and PKCalpha cause activation and translocation of NF-kappaB to the nucleus, which, in turn, results in induction of ICAM-1. Induction of ICAM-1 on aortic endothelium stimulates monocyte:endothelial adhesion in vivo in apoEKO mice.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

12/15-lipoxygenase regulates intercellular adhesion molecule-1 expression and monocyte adhesion to endothelium through activation of RhoA and nuclear factor-kappaB.

BACKGROUND 12/15-lipoxygenase (12/15-LO) activity leads to the production of the proinflammatory eicosanoids 12-S-hydroxyeicosatetraenoic acid (12SHETE) and 13-S-hydroxyoctadecadienoic acid. We have previously shown a 3.5-fold increase in endothelial intercellular adhesion molecule (ICAM)-1 expression in mice overexpressing the 12/15-LO gene. We examined whether 12/15-LO activity regulated endo...

متن کامل

Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs.

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-kappaB-dependent pro-inflammator...

متن کامل

Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.

OBJECTIVE Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis. METHODS AND RESULTS We crossed C57BL/6 Pecam1(-/-) mice with apolipoprotein E-deficient (Apoe(-/...

متن کامل

Oral flavonoid supplementation attenuates atherosclerosis development in apolipoprotein E-deficient mice.

OBJECTIVE Caffeic acid phenethyl ester (CAPE), a natural flavonoid, specifically blocks activation of nuclear factor-kappaB (NF-kappaB). We examined the effects of oral CAPE supplementation on atherogenesis in apolipoprotein E-deficient (apoE-/-) mice. METHODS AND RESULTS Ten-week-old male apoE-/- mice were supplemented orally with CAPE (30 mg/kg body weight) for 12 weeks. At the end of admin...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 26 6  شماره 

صفحات  -

تاریخ انتشار 2006