Doxycycline affects diet- and bacteria-associated atherosclerosis in an ApoE heterozygote murine model: Cytokine profiling implications
Doxycycline affects diet- and bacteria-associated atherosclerosis in an ApoE heterozygote murine model: Cytokine profiling implications
复制标题
DOI：
10.1016/j.atherosclerosis.2006.02.026
复制
发表时间：
2007-01-01
期刊：
影响因子：
5.3
通讯作者：
Amar, Salomon
中科院分区：
文献类型：
--
作者：
Madan, Monika;Bishayi, Biswadev;Amar, Salomon
背景资料：据推测，全身感染病原体，如牙龈卟啉单胞菌（Pg），提高炎症反应，增加动脉粥样硬化的易感性。我们假设，多西环素将是有益的饮食和/或PG诱导的动脉粥样硬化给予其在各种细胞功能和matrix remodeling.Methods和结果的作用：ApoE +/-小鼠每周接种Pg和治疗与多西环素或生理盐水;动物被喂食高脂肪或饲料。在14或24周时对动物实施安乐死，并进行近端主动脉粥样硬化病变的组织形态计量学分析、SAA水平和血清细胞因子谱分析。组织形态学分析表明，在喂食高脂饮食的未感染小鼠中，强力霉素治疗导致平均病变从10.5% +/- .49减少到1.09% +/- 0.102 14周时从21.5% +/- 6.49降至8.26% +/- 0.162（p = 0.106）。用多西环素处理的喂食饲料的Pg小鼠也导致在14周时从0.62% +/- 0.128降低至0.0% +/- 0.0（p < 0.05），并且在24周时从0.92% +/- 0.23降低至0.0% +/- 0.0（p < 0.05）。对喂食高脂饮食并接种Pg的小鼠给予强力霉素导致动脉粥样化病变的平均百分比从16.46% +/- 1.69降低至1.141% +/- 0.23在14周时从25.27% +/- 1.734降低到0.428% +/- 0.033（P < 0.05）。在这个时间点，多西环素治疗组和高脂饮食组感染PG的动物的SAA水平分别降低了5倍和3倍。细胞因子抗体阵列显示，无论是PG感染还是高脂饮食，多西环素治疗组的促炎细胞因子水平显著降低，而抗炎细胞因子不受影响。与强力霉素对基质蛋白酶的作用一致，在24周时，血清MMP-9水平显著降低60%。（p < 0.05）和30%（p < 0.05）分别在Pg感染的高脂肪和普通饮食组中用强力霉素治疗。在ApoE +/-Pg接种和/或高脂肪饮食喂养的小鼠中，多西环素降低促炎细胞因子并导致动脉粥样硬化减少。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Background: It has been postulated that systemic infection with pathogens such as Porphyromonas gingivalis (Pg) elevates the inflammatory response and increases susceptibility to atherosclerosis. We hypothesized that Doxycycline would be beneficial in diet- and/or Pg-induced atherosclerosis given its role in various cell functions and matrix remodeling.Methods and results: ApoE +/- mice were inoculated weekly with Pg and treated with either Doxycycline or saline; animals were fed either a high-fat or chow diet. Animals were euthanized at 14 or 24 weeks and histomorphometric analysis of atheromatous lesions in proximal aorta, levels of SAA and serum cytokine profiling were performed. Histomorphometric analysis demonstrated that in non-infected mice fed a high fat diet, Doxycycline treatment resulted in a reduction of mean lesions from 10.5% +/- .49 to 1.09% +/- 0.102 (P < 0.05) at 14 weeks and a reduction from 21.5% +/- 6.49 to 8.26% +/- 0.162 (p = 0.106) at 24 weeks. Chow-fed Pg mice treated with Doxyclycline also resulted in a reduction from 0.62% +/- 0.128 to 0.0% +/- 0.0 (p < 0.05) at 14 weeks and a reduction from 0.92% +/- 0.23 to 0.0% +/- 0.0 (p < 0.05) at 24 weeks. Administration of Doxycycline to mice fed a high fat diet and Pg-inoculated resulted in a reduction of mean percentage of atheromatous lesions from 16.46% +/- 1.69 to 1.141% +/- 0.23 (p < 0.05) at 14 weeks and a reduction from 25.27% +/- 1.734 to 0.428% +/- 0.033 (P < 0.05) at 24 weeks. At this timepoint, SAA levels in Pg-infected animals were reduced by five-fold and three-fold in Doxycycline-treated chow and high fat-diet groups, respectively. Cytokine antibody arrays revealed a marked reduction in the levels of pro-inflammatory cytokines in Doxycycline-treated groups whether Pg-infected or fed a high fat diet while anti-inflammatory cytokines were not affected. Consistent with the role of Doxycycline on matrix proteases, at 24 weeks MMP-9 Serum levels were markedly reduced by 60% (p < 0.05) and 30% (p < 0.05) with Doxycycline treatment in Pg-infected high fat and chow diet groups, respectively.Conclusions: Doxycycline decreases pro-inflammatory cytokines and results in reduction of atherosclerosis in ApoE +/- Pg-inoculated and/or high fat diet fed mice. (c) 2006 Elsevier Ireland Ltd. All rights reserved.