| Background and purpose minimally modified low density lipoprotein(mm LDL) is the LDL which only part of the lipids were oxidized,the lysine residues in Apolipoprotein B100 structure were not destroy.In vitro organ and cell culture studies we found that mm LDL can significant up-regulation the cardio cerebral vascular smooth muscle of endothelin B receptor,enhance the contractilityof vascular;mm LDL can also combined with TLR4 in macrophage cells,priming the immune response induced generous inflammatory factor produced,the function of cell phagocytosis were changed,accelerated the formation of foam cells.In our previous research,mm LDL can significant reduce the function of endothelium-dependent vascular relaxation,mainly through up-regulation the expression of TLR4 induce immune response which destroy the endothelial cell ultrastructure.But so far,the role of mm LDL to vascular smooth muscle receptor was less reported.In our experiment,we aimed at effects and molecular mechanism of mm LDL to alpha receptor in mesenteric artery which provide some theoretical guidance and experimental basis for the study on anti cardiovascular and cerebrovascular diseases and provide targets for new ideas and new drug therapy.Method Three groups were designed in our experiment:1)Saline group(NS);2)The tail vein injection with mm LDL group(mm LDL);3)The tail vein injection with mm LDL and intraperitoneal injection U0126(mm LDL+U0126).U0126 was a specific inhibitor of ERK1/2 and injected intraperitoneally with 2h before mm LDL were injected.Drug injection time was 96 h,the mice were put to death after injection,take mouse mesenteric artery.The vascular tension of mice mesenteric artery induced by NA were measured by DMT.The Serum concentration of ox LDL,TNF-α and IL-1β were measured by Elisa kits,RT-PCR、Western Blotting were used detection the expression of α1 receptor、α2 receptor、TNF-α、IL-1β and p ERK1/2.Result U0126 can significant depressed the function of vascular contraction induced by α receptor, the value of Emax reduced from(161±11)% to(130±11)%(P < 0.01), the value of EC50 reduced from 6.20±0.07 to 5.75±0.14(P < 0.05).Investigate the subtype of α receptor,use α1 receptor antagonist prazosin, the dose-response curves of NA parallel to the right with no significant change of Emax value, PA2 is 10.91 ± 0.28.But we use α2 receptor antagonist yohimbine, the dose-response curves of NA parallel to the right with no significant change of Emax value, PA2 is 7.28 ± 0.24.mm LDL can up regulation the expression of α1 receptor, which was inhibited by U0126. The m RNA level of α1 receptor reduced from 8.21±0.56 to 1.24±0.07(P < 0.001),protein level reduced from 1.31±0.03 to 0.93±0.05(P < 0.01). But have no effect of α2 receptor. After intravenous injection of mm LDL, the expression of p ERK1/2 was up-regulation from 0.50±0.01 to 0.83 ± 0.01(P < 0.01); Intraperitoneal injection of U0126, reduced from 0.83±0.01 to 0.49 ± 0.01(P < 0.01). mm LDL also increased the expression of TNF-α and IL-1β serum concentration m RNA and protein level,TNF-α serum concentration increased from 117.4 ± 2.7 pg/m L to 264.8 ± 4.6 pg/m L(P < 0.01),m RNA increased from 0.99 ± 0.01 to 6.80 ±0.21(P < 0.001),protein increased from 0.39 ± 0.01 to 0.59 ±0.01(P < 0.01);IL-1βincreased from 30.0±3.0 pg/m L to 67.2 ± 4.5 pg/m L(P < 0.01),m RNA increased from 1.01 ± 0.04 to 3.27 ±0.01;which was inhibited by U0126,The serum concentration IL-1β, TNF-α were positive correlation with the Emax of NA.Conclusion mm LDL activates the ERK1/2 signal transduction pathway to increase the levels of TNF-α and IL-1β and the expression of the α1 receptor in vascular smooth muscles to strengthen α1 receptor-mediated vasoconstriction. |
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