Abstract 5456: Vascular Endothelial Cells Endothelin-1 Deficiency Decreased Vascular Protection in Atherosclerosis Mouse Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Dyah Wulan Anggrahini ◽  
Noriaki Emoto ◽  
Kazuhiko Nakayama ◽  
Bambang Widyantoro ◽  
Kazuya Miyagawa ◽  
...  

Endothelium plays important role in protective mechanism of vascular wall. The balance between endothelin-1 (ET-1) and nitric oxide provide endothelial barrier to lipoprotein retain and macrophage recruitment. In contrasts, ET-1 is also a strong vasoconstrictor. In this study, we aim to determine the role of vascular endothelial cells-derived ET-1 in the development of atherosclerosis. For that purpose, we crossbred Vascular Endothelial Cells-specific ET-1 Knockout (VEETKO) mice to ApoEKO mice. ApoE/VEET-DKO exhibited significantly lower ET-1 plasma and mRNA level as compared to ApoEKO mice. No significant differences of blood pressure, plasma cholesterol or lipid profiles were observed in both mice. Surprisingly, after 8 weeks of western diet, we found that the atherosclerotic lesion was exaggerated in the aortic sinus and brachiochepalic artery of ApoE/VEET-DKO mice (n=7) as compared to those of ApoEKO mice (n=7) (ratio/vessel wall, 0.93±0.13vs.0.49±0.09, p<0.05). We further showed the increase in macrophage plaque content and peritoneal macrophage recruitment in DKO mice. To understand the mechanism of vascular protection, we found lower eNOS mRNA level in DKO mice despite only lower tendency of ETB receptor expression. Functionally, the mice lacking ET-1 in endothelial cells showed impaired NO-mediated endothelial function. Decreased vascular protection further led to increase plaque instability in DKO mice. Here we showed that plaque of DKO mice was more lipid enrich as compared to that of ApoEKO (ratio/lesion, 0.56±0.03vs.0.42±0.04, p<0.05). Moreover, lack of ET-1 significantly reduced matrix synthesis following lower SMCs accumulation in the lesion (ratio/vessel wall, 0.28±0.06vs.0.57±0.08, p<0.05), which was mediated by TGFβ. Interestingly, despite similar advance-typed lesion formed, 15% of DKO mice exhibited plaque hemorrhage in brachiochepalic artery. In conclusion, we demonstrated the increase in atherosclerosis and plaque instability in our model. This further suggests that ET-1 produced from vascular endothelial cells is required for protective mechanism in vascular wall in balance with nitric oxide production. Our data imply for the careful monitoring in the use of ET receptor antagonist in clinical setting.

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Taiki Kida ◽  
Yoshiki Tsubosaka ◽  
Masatoshi Hori ◽  
Hiroshi Ozaki ◽  
Takahisa Murata

Objective TGR5, a membrane-bound, G-protein-coupled receptor for bile acids, is known to be involved in regulation of energy homeostasis and inflammation. However, little is known about the function of TGR5 in vascular endothelial cells. In the present study, we examined whether TGR5 agonism represents anti-inflammatory effects in vascular endothelial cells focusing on nitric oxide (NO) production. Methods and Results In human umbilical vein endothelial cells (HUVECs), treatment with taurolithocholic acid (TLCA), which has the highest affinity to TGR5 among various bile acids, significantly reduced tumor necrosis factor (TNF)-α-induced vascular cell adhesion molecule (VCAM)-1 protein expression and adhesion of human monocytes, U937. These effects were abrogated by a NO synthase (NOS) inhibitor, N G -Monomethyl-L-arginine (L-NMMA). In bovine aortic endothelial cells (BAECs), treatment with TLCA as well as lithocholic acid, which also has high affinity to TGR5, significantly increased the NO production. In contrast, deoxycholic acid and chenodeoxycholic acid, which possess low affinity to TGR5, did not affect the NO production. Gene depletion of TGR5 by siRNA transfection abolished TLCA-induced NO production in BAECs. TLCA-induced NO production was also observed in HUVECs measured as intracellular cGMP accumulation. We next investigated the signal pathways responsible for the TLCA-induced NO production in endothelial cells. Treatment with TLCA increased endothelial NOS (eNOS) ser1177 phosphorylation in HUVECs. This response was accompanied by increased Akt ser473 phosphorylation and intracellular Ca 2+ ([Ca 2+ ] i ). Treatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or blockade of calcium channel with La 3+ , significantly decreased TLCA-induced eNOS ser1177 phosphorylation and subsequent NO production. Conclusion These results indicate that TGR5 agonism can mediate anti-inflammatory responses by suppressing VCAM-1 expression and monocytes adhesion to endothelial cells. This function is dependent on NO production via Akt activation and [Ca 2+ ] i increase.


2010 ◽  
Vol 58 (11) ◽  
pp. 6960-6965 ◽  
Author(s):  
Kazuo Shimizu ◽  
Mikako Sato ◽  
Youzuo Zhang ◽  
Tomomi Kouguchi ◽  
Yoshihisa Takahata ◽  
...  

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P169-P169
Author(s):  
Shigetoshi Yoda ◽  
Fukushima Hisaki ◽  
Nishiike Suetaka ◽  
Shibata Dai ◽  
Tamotsu Harada

Objectives Several studies have reported that inducible nitric oxide synthase (iNOS) was expressed within the epithelial cell of the trachea in asthmic patients and asthmic model animals. However, neither appearance nor localization of iNOS in the nasal mucosa of allergic rhinitis has been examined. This research clarifies expression and the localization of iNOS in the nasal mucosa of allergic rhinitis by using the allergic model mice. Methods Allergic rhinitis was induced in male mice at 6 weeks of age using purified Japanese cedar pollen allergen (Cry j 1). Cry j 1 was injected 2 times into the abdomen (day 0 and 4) and administered intranasally for 7 consecutive days (day 9–15). On day 22, the expression and localization of iNOS in nasal mucosa of both allergic rhinitis model and control mice were examined by immunohistochemistry. Results In control mice, the expression of iNOS was localized in olfactory nerve, nasal gland beneath the respiratory epithelium and vascular endothelial cells. In allergic rhinitis group, the expression of iNOS was not only localized in olfactory nerve, nasal gland, and vascular endothelial cells, but also in olfactory epithelium and respiratory epithelium. Conclusions The expression of iNOS was increased in olfactory epithelium and respiratory epithelium of allergic rhinitis mice compared with controls.


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