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- Title
S17834 Attenuates Atherosclerosis in Insulin Resistant LDLr<sup>-/-</sup> Mice--Regulation of VCAM-1 and iNOS.
- Authors
Xu, Shanqin; Maitland, Karlene A.; Hou, Xiuyun; Zang, Meng-wei; Zuccollo, Adriana; Verbeuren, Tony J.; Cohen, Richard A.; Jiang, Bingbing
- Abstract
S17834 is a synthetic polyphenol (hydroxy triallyl farnisine) that attenuates atherogenesis in type 1 diabetic LDLr[sup -/-] mice. The objective of this study was to examine its role in influencing atherogenesis and the expression of NF-κB-inducible genes, vascular cell adhesion molecule (VCAM)-1 and inducible nitric oxide synthase (iNOS) in insulin resistant LDLr[sup -/-] mice fed a high fat high sucrose diet (HFHS, 30% fat and 30% sucrose) for 6 wks. HFHS LDLr[sup -/-] mice developed significantly more atherosclerotic lesions in the aortic root than did LDLr[sup -/-] mice on normal chow [25±1.9 vs. 6±0.4 x 1000 µm² (n=8), respectively, P<0.001]. S17834 (130 mg/kg/day, in HFHS diet) significantly attenuated lesions in HFHS LDLr[sup -/-] mice [10±l.l xl000 µm² (n=8), P<0.001]. Immunohistochemical staining showed that HFHS diet increased VCAM-1, but decreased iNOS expression in aortic lesions compared to LDLr[sup -/-]mice on normal chow, and that this was reversed by S17834. Mechanistic studies in cultured rat vascular smooth muscle cells show that S17834 reduced IL-1β-induced VCAM-1 expression, but enhanced IL-1β-induced iNOS expression and NO production. Although S17834 alone did not induce iNOS expression, it enhanced IL-1β-induced ERK-activation which is responsible for prolonged NF-κB activity and iNOS expression. Furthermore, EGF-induced DNA synthesis ([³H]-thymidine incorporation) was reduced 62% by IL-1β alone (P<0.01) and 70% by IL-1β plus S17834 (P<0.01), which was partially reversed by L-NMMA. S17834 alone inhibited 52% of EGF-induced [³H]-thymidine incorporation (P<0.01), suggesting that both NO-dependent and independent mechanisms were involved in the anti-proliferative action. In conclusion, the anti-atherogenic effect of S17834 may relate to regulating the inflammatory process by reducing VCAM-1 expression, enhancing iNOS expression, and inhibiting smooth muscle cell proliferation.
- Subjects
POLYPHENOLS; ATHEROSCLEROSIS; INSULIN resistance; LOW density lipoproteins; CELL adhesion molecules; NITRIC-oxide synthases; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA192
- ISSN
0012-1797
- Publication type
Article