Abstract 380: Vascular Pcsk9: A Mediator for Atherogenesis Independent of LDL Receptor

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hua Sun ◽  
Michael Tan ◽  
Ba-bie Teng
Keyword(s):  
Endothelial Cells ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Degradation Process ◽  
Double Knockout ◽  
Aortic Endothelial Cells ◽  
Apob Mrna ◽  
Pcsk9 Gene ◽  
Atherosclerotic Lesions

PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases the LDL levels by binding to hepatocyte LDL receptors (LDLR) and subjects it to degradation. We show that PCSK9 regulates apolipoprotein B (apoB) production by inhibiting its degradation process via the autophagic pathway, irrespective of the presence of LDLR. In addition to the role of PCSK9 in promoting hyperlipidemia, we hypothesized that vascular-PCSK9 in endothelial cells (EC) plays a role in initiating atherogenesis, irrespective of the presence of LDL receptor. Our laboratory has generated double knockout mice lacking both LDLR and Apobec1 (apoB mRNA editing enzyme), named LDb, Ldlr-/-Apobec1-/-. They have the lipoprotein phenotype mimics human with hyperlipidemia; elevated levels of VLDL and LDL with low levels of HDL. They develop atherosclerotic lesions spontaneously. To investigate the role of PCSK9 in atherogenesis, we deleted Pcsk9 gene from LDb mice to generate the triple knockout mice (named LTp, Ldlr-/-Apobec1-/-Pcsk9-/-). In comparison to LDb mice (n=14), the LTp mice (n=8) had significantly decreased levels of cholesterol (387±10 vs. 313±14 mg/dl; p<0.0008) and triglyceride (304±15 vs. 204±2.3 mg/dl; p<0.0002). However, despite their high cholesterol levels at over 300 mg/dl, the atherosclerotic lesions in LTp mice were significantly decreased in comparison to LDb mice (8.8%±3.5 vs. 24%±3.3, p=0.004, n=5 vs. 5). We hypothesized that vascular PCSK9 regulates the development of atherosclerosis. We incubated LDL containing PCSK9 (LDL/PCSK9) on primary aortic endothelial cells (EC) obtained from LDb or LTp to study the effects of LDL/PCSK9 on inflammation. We show that LDL/PCSK9 could not induce the expressions of Lox-1, TLR-2, or ICAM-1 in EC from LTp, resulting in absence responses on proinflammatory markers (CCL2 and CCL7) and autophagic molecules (p62 and TRAF6). In conclusion, our results suggest that vascular PCSK9 play an essential role in atherogenesis.

ICAM-1 deficiency reduces atherosclerotic lesions in double knockout mice (apo-E−/−/ICAM-1−/−) fed a fat or a chow diet

1999 ◽  
Vol 144 ◽  
pp. 166-167
Author(s):  
M.C. Bourdillon ◽  
C. Covacho ◽  
R.N. Poston ◽  
E. Chignier ◽  
G. Canard ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Chow Diet ◽  
Double Knockout ◽  
Atherosclerotic Lesions ◽  
Apo E

Adenoviral expression of 15-lipoxygenase-1 in rabbit aortic endothelium: role in arachidonic acid-induced relaxation

2007 ◽  
Vol 292 (2) ◽  
pp. H1033-H1041 ◽  
Author(s):  
Nitin T. Aggarwal ◽  
Blythe B. Holmes ◽  
Lijie Cui ◽  
Helena Viita ◽  
Seppo Yla-Herttuala ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Arachidonic Acid ◽  
Rabbit Aorta ◽  
Epoxyeicosatrienoic Acid ◽  
Aortic Endothelial Cells ◽  
Aortic Endothelium ◽  
Rate Limiting Step ◽  
Immunohistochemical Studies ◽  
Rate Limiting

Endothelium-dependent vasorelaxation of the rabbit aorta is mediated by either nitric oxide (NO) or arachidonic acid (AA) metabolites from cyclooxygenase (COX) and 15-lipoxygenase (15-LO) pathways. 15-LO-1 metabolites of AA, 11,12,15-trihydroxyeicosatrienoic acid (THETA), and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) cause concentration-dependent relaxation. We tested the hypothesis that in the 15-LO pathway of AA metabolism, 15-LO-1 is sufficient and is the rate-limiting step in inducing relaxations in rabbit aorta. Aorta and rabbit aortic endothelial cells were treated with adenoviruses containing human 15-LO-1 cDNA (Ad-15-LO-1) or β-galactosidase (Ad-β-Gal). Ad-15-LO-1-transduction increased the expression of a 75-kDa protein corresponding to 15-LO-1, detected by immunoblotting with an anti-human15-LO-1 antibody, and increased the production of HEETA and THETA from [14C]AA. Immunohistochemical studies on Ad-15-LO-1-transduced rabbit aorta showed the presence of 15-LO-1 in endothelial cells. Ad-15-LO-1-treated aortic rings showed enhanced relaxation to AA (max 31.7 ± 3.2%) compared with Ad-β-Gal-treated (max 12.7 ± 3.2%) or control nontreated rings (max 13.1 ± 1.6%) ( P < 0.01). The relaxations in Ad-15-LO-1-treated aorta were blocked by the 15-LO inhibitor cinnamyl-3,4-dihydroxy-a-cyanocinnamate. Overexpression of 15-LO-1 in the rabbit aortic endothelium is sufficient to increase the production of the vasodilatory HEETA and THETA and enhance the relaxations to AA. This confirms the role of HEETA and THETA as endothelium-derived relaxing factors.

Endothelium-derived relaxant factor inhibits effects of nitrocompounds in isolated arteries

1987 ◽  
Vol 252 (2) ◽  
pp. H307-H313
Author(s):  
U. Pohl ◽  
R. Busse
Keyword(s):  
Endothelial Cells ◽  
Femoral Artery ◽  
Response Curve ◽  
Rabbit Aorta ◽  
Nordihydroguaiaretic Acid ◽  
Aortic Endothelial Cells ◽  
Bovine Aortic Endothelial Cells ◽  
Basal Release ◽  
Isolated Arteries

We investigated the influence of endothelial cells on the smooth muscle vasodilator effects to sodium nitroprusside (SNP) or Teopranitol (an organic mononitrate) in isolated segments of rabbit aorta and femoral artery. In the femoral artery, the vasodilator responses to both nitrocompounds were significantly higher in the absence of endothelial cells or after pretreatment with the endothelium-derived relaxant factor (EDRF) inhibitor nordihydroguaiaretic acid (NDGA; 10 microM). Moreover, under conditions of stimulated EDRF release (induced by acetylcholine; 30–100 nM) the vasodilator responses to SNP were further attenuated in vessels with intact endothelium. By contrast, in the rabbit aorta, the vasodilator responses to the nitrocompounds were not significantly altered by either endothelium removal or treatment with NDGA. However, in the presence of the EDRF stimulator acetylcholine, the dose-response curve to SNP was shifted to right in the aorta as well. The role of EDRF in the endothelium-mediated attenuation of the dilator potency of SNP was further investigated by using EDRF released from cultured (bovine aortic) endothelial cells. The dilator effects of SNP were compared in endothelium denuded femoral or aortic segments in the presence or absence of EDRF. The vasodilator effects of SNP in both types of arteries were significantly reduced in the presence of EDRF. We conclude that EDRF attenuates the arterial vasodilation induced by SNP and Teopranitol. The results further suggest that endothelial cells exhibit a greater basal release of EDRF in the femoral artery than in the aorta, since under unstimulated conditions an EDRF-induced attenuation was seen only in femoral and not in aortic segments.

scholarly journals mRNA-Binding Protein ZFP36 Is Expressed in Atherosclerotic Lesions and Reduces Inflammation in Aortic Endothelial Cells

2013 ◽  
Vol 33 (6) ◽  
pp. 1212-1220 ◽  
Author(s):  
Huanchun Zhang ◽  
W. Robert Taylor ◽  
Giji Joseph ◽  
Valentina Caracciolo ◽  
Donna M. Gonzales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Binding Protein ◽  
Aortic Endothelial Cells ◽  
Atherosclerotic Lesions ◽  
Mrna Binding Protein ◽  
Mrna Binding ◽  
Aortic Endothelial

Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2

2005 ◽  
Vol 289 (5) ◽  
pp. C1134-C1144 ◽  
Author(s):  
Yun Fang ◽  
Gernot Schram ◽  
Victor G. Romanenko ◽  
Congzhu Shi ◽  
Lisa Conti ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Dominant Role ◽  
Functional Expression ◽  
Inward Rectifier ◽  
Dominant Negative ◽  
Current Sensitivity ◽  
Aortic Endothelial Cells ◽  
Human Aortic Endothelial Cells ◽  
Aortic Endothelial

Inward rectifier K+ channels (Kir) are a significant determinant of endothelial cell (EC) membrane potential, which plays an important role in endothelium-dependent vasodilatation. In the present study, several complementary strategies were applied to determine the Kir2 subunit composition of human aortic endothelial cells (HAECs). Expression levels of Kir2.1, Kir2.2, and Kir2.4 mRNA were similar, whereas Kir2.3 mRNA expression was significantly weaker. Western blot analysis showed clear Kir2.1 and Kir2.2 protein expression, but Kir2.3 protein was undetectable. Functional analysis of endothelial inward rectifier K+ current ( IK) demonstrated that 1) IK current sensitivity to Ba2+ and pH were consistent with currents determined using Kir2.1 and Kir2.2 but not Kir2.3 and Kir2.4, and 2) unitary conductance distributions showed two prominent peaks corresponding to known unitary conductances of Kir2.1 and Kir2.2 channels with a ratio of ∼4:6. When HAECs were transfected with dominant-negative (dn)Kir2.x mutants, endogenous current was reduced ∼50% by dnKir2.1 and ∼85% by dnKir2.2, whereas no significant effect was observed with dnKir2.3 or dnKir2.4. These studies suggest that Kir2.2 and Kir2.1 are primary determinants of endogenous K+ conductance in HAECs under resting conditions and that Kir2.2 provides the dominant conductance in these cells.

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