Blockade of scavenger receptor class B type I raises high density lipoprotein cholesterol levels but exacerbates atherosclerotic lesion formation in apolipoprotein E deficient mice

2006 ◽  
Vol 58 (12) ◽  
pp. 1629-1638 ◽  
Author(s):  
Ken Kitayama ◽  
Tomohiro Nishizawa ◽  
Koji Abe ◽  
Kenji Wakabayashi ◽  
Tomiichiro Oda ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Type I ◽  
Lesion Formation ◽  
Cholesterol Levels ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Abstract 624: Endothelial Scavenger Receptor Class B, Type I (SR-BI) Mediates LDL Uptake by the Artery Wall and Promotes Atherosclerosis in Hypercholesterolemic Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Linzhang Huang ◽  
Ken Chambliss ◽  
Mohamed Ahmed ◽  
Chieko Mineo ◽  
Philip W Shaul
Keyword(s):  
Endothelial Cells ◽  
Scavenger Receptor ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Type I ◽  
Artery Wall ◽  
Blocking Antibody ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Ldl Uptake

In endothelial cells, high density lipoprotein cholesterol (HDL) binding to scavenger receptor class B, type I (SR-BI) promotes the production of the antiatherogenic signaling molecule nitric oxide (NO) and also endothelial repair. To study how SR-BI in endothelium impacts atherosclerosis, we bred newly-created floxed SR-BI mice, vascular endothelial cadherin promoter-driven Cre recombinase transgenic (VECad-Cre), and apoE -/- mice to generate apoE -/- with normal endothelial SR-BI expression (SR-BI ECIN ;apoE -/- ) or selective deletion of SR-BI from endothelium (SR-BI ECOUT ;apoE -/- ). At weaning all mice were placed on an atherogenic diet (20% fat, 1.25% cholesterol), and plasma lipid profiles and atherosclerosis were evaluated 8 weeks later. Endothelial deletion of SR-BI did not alter the plasma lipid profile. Surprisingly, male SR-BI ECOUT ;apoE -/- mice displayed 63% less atherosclerosis in the en face aorta than male SR-BI ECIN ;apoE -/- mice, aortic root lesions were comparably affected, and similar findings were obtained in females. Recognizing that SR-BI binds both HDL and low density lipoprotein cholesterol (LDL), to then discern how endothelial SR-BI promotes atherosclerosis we determined using Di-I-labeled oxidized LDL (oxLDL) if SR-BI influences oxLDL uptake by endothelial cells. Such uptake is the first step in the endothelial transcytosis that delivers LDL to the artery wall to initiate atherogenesis. OxLDL uptake by primary human aortic endothelial cells was blunted by 87% by SR-BI blocking antibody, and it was also decreased by SR-BI deletion via siRNA, and by the chemical inhibitor of SR-BI BLT-1. Furthermore, SR-BI blocking antibody and BLT-1 caused marked declines in endothelial oxLDL transcytosis. Moreover, 4 hours following IV administration, oxLDL uptake in aorta was decreased by 84% in SR-BI ECOUT ;apoE -/- versus SR-BI ECIN ;apoE -/- mice. These collective findings indicate that endothelial SR-BI plays an important role in atherogenesis, and that it likely does so by mediating LDL uptake into the artery wall. They further suggest that there are mechanisms that govern LDL transport across endothelium that may be targeted to provide novel means to combat atherosclerosis.

scholarly journals α-Tocopherol Metabolism Is Abnormal in Scavenger Receptor Class B Type I (SR-BI)-Deficient Mice

2002 ◽  
Vol 132 (3) ◽  
pp. 443-449 ◽  
Author(s):  
Pablo Mardones ◽  
Pablo Strobel ◽  
Soledad Miranda ◽  
Federico Leighton ◽  
Verónica Quiñones ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Type I ◽  
Scavenger Receptor Class ◽  
Class B ◽  
Deficient Mice

scholarly journals Binding of High Density Lipoprotein (HDL) and Discoidal Reconstituted HDL to the HDL Receptor Scavenger Receptor Class B Type I

2000 ◽  
Vol 275 (28) ◽  
pp. 21262-21271 ◽  
Author(s):  
Kalliopi N. Liadaki ◽  
Tong Liu ◽  
Shangzhe Xu ◽  
Brian Y. Ishida ◽  
Philippe N. Duchateaux ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
High Density ◽  
Type I ◽  
Scavenger Receptor Class ◽  
Class B

scholarly journals The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4128-4132 ◽  
Author(s):  
Johan Bourghardt ◽  
Göran Bergström ◽  
Alexandra Krettek ◽  
Sara Sjöberg ◽  
Jan Borén ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Low Dose ◽  
Hormone Replacement ◽  
Atherosclerotic Lesion ◽  
Total Serum ◽  
High Dose ◽  
Lesion Formation ◽  
Cholesterol Levels ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17β-estradiol (6 μg/d), or 2-methoxyestradiol [6.66 μg/d (low-dose) or 66.6 μg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

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