米诺环素对5-LOX通路及动脉粥样硬化中炎症反应的抑制作用

Minocycline Suppresses Vascular Inflammation and Atherosclerosis in Apo E^(-/-) mice Via 5-LOX Pathway

目的米诺环素对5-LOX通路及动脉粥样硬化(atherosclorosis,AS)中炎症反应的抑制作用。方法以高脂喂养Apo E-/-小鼠建立AS模型,同时给予米诺环素或辛伐他汀治疗12周。比较各组小鼠的血脂水平,5-LOX的表达及其代谢物LTB4的含量;测定小鼠主动脉AS斑块的面积及斑块组成(脂质、胶原和巨噬细胞含量);PCR方法比较小鼠主动脉中相关炎症因子TNF-α、IL-6、VCAM-1、MMP-2、MMP-9 m RNA的含量。结果米诺环素能显著减少主动脉中5-LOX的表达及血液中LTB4的含量;降低小鼠主动脉中相关炎症因子TNF-α、IL-6、VCAM-1、MMP-2、MMP-9 m RNA的含量。在AS斑块的形成和发展中,米诺环素显著降低了Apo E-/-小鼠AS斑块的面积,减少斑块中巨噬细胞的含量并增加胶原的含量,提高斑块的稳定性。但是米诺环素没有改变Apo E-/-小鼠的血脂水平。结论米诺环素有抗AS的作用,其作用可能与其对5-LOX通路及炎性细胞和炎症介质的抑制作用有关。

OBJECTIVE To investigate the mechanisam of minocycline on inflammation and atherosclerosis in Apo E-/- mice. METHODS Eight-week old Apo E-/- mice were assigned randomly into two groups： model group, minocycline（12 mg·kg？1） and simvastatin group（5 mg·kg？1）. The mice were sacrificed after 12 weeks. The plasma total cholesterol, triglyceride, HDL and LDL concentration were measured. The lesion of atherosclerosis was observed pathological staining. Inflammatory cytokines were measured by real-time PCR. The plasma concentration of LTB4 and expression of 5-LOX was also measured by ELISA and Western blotting. RESULTS Minocycline significantly ameliorated the formation of typical atheromatous lesions in Apo E-/- mice, and reduced macrophage content in the atheromatous lesions of the aortic arch concomitant with upregulation the amount of collagen, which lead to stable atheromatous plaques. These findings were supported by results showing that aortic MCP-1, IL-6, TNF-α, VCAM-1, MMP-2 and MMP-9 expression was decreased by minocycline. Minocycline also reduced the plasma concentration of LTB4 and aortic expression of 5-LOX. CONCLUSION Minocycline effectively attenuated atherosclerosis in mouse model, suggesting its therapeutic potential for atherosclerosis. The anti-atherogenic effect of minocycline might be associated with its inhibition on 5-LOX pathway.