The Effect And Mechanisms Of RXR/VDR Agnoists On Atherosclerosis In STZ-induced Diabetes Apoe-knock Out Mice

Aim To explore the effect of retinoid X receptor agonist(bexarotene) or vitaminD receptor agonist(calcitriol) on the development of atherosclerosis in streptozotocin-induced diabetic apolipoprotein E knockout (STZ-ApoE-/-) mice.Methods Seventy male mice were treated for12weeks as follows:(1)C57+vehicle;(2)ApoE-/-+vehicle;(3)STZ-ApoE-/-+vehicle;(4)STZ-ApoE-/-+bexarotene(10mg/kg/d);(5)STZ-ApoE-/-+calcitriol(200ng/kg,twice a week);(6)STZ-ApoE-/-+bex(10mg/kg/d)+cal(200ng/kg, twice a week). Fifty ApoE-/-mice were injected intraperitoneally ofstreptozotocin to establish diabetic animal model. The plaque area in the thoracicaorta was measured using H-E staining. Reverse transcription-polymerase ChainReaction (RT-PCR) and Western blotting methods were used to detect the levels ofgp91、NF-κB、VDR、RXRα. We were using immunohistochemical method toobserve the distribution of gp91、NF-κB in the thoracic artery of STZ-induceddiabetes ApoE-Knock out mice. To detect the level of MDA、 SOD and theinflammatory cytokines, chemical methods and Elisa Kit were used to detect inSTZ-induced diabetes ApoE-Knock out mice.Results1) In the STZ-induced diabetes ApoE-/-mice，the levels of fastingblood glucose、blood lipid、gp91、MDA、SOD、NF-κB P65、and IL-6were greatlyincreased (P<0.05).2) The levels of fasting blood glucose and TC/LDL-C in Bex andCal groups were not significantly changed. However, the plaque area of thoracicartery and the levels of gp91、NF-κB P65、and IL-6in Bex and Cal groups weredecreased, After teeated with bexarotene, the level of HDL was increased, and thelevel of MDA was decreased. In B+C group, these Inhibition effects of gp91、MDA、NF-κB P65、IL-6are more significant, at the same time, the activity of SOD wasgreatly increased (P<0.05).3) In the STZ-induced diabetes ApoE-/-mice，the levels of RXRα、VDR were greatly weakened (P<0.05). The levels of VDR mRNA andprotein expression were increased in Cal and B+C groups; after treated withbexarotene, the levels of RXRαmRNA and protein expression in Bex group wereincreased, but the levels of RXRαmRNA and protein expression in Cal group wereinhibited(P<0.05). Compared with Cal group, the expression of RXRαin B+C groupwas remarkably increased(P<0.05).Conclusion Bexarotene or calcitriol decreases the development ofatherosclerosis in streptozotocin-induced diabetic ApoE-/-mice, combination therapyaffords greater protection than monotherapy. The mechanism maybe involved inresisting the activation of NADPH oxidant enzyme and NF-κB, and inhibiting theinflammation response.