Wang Qun, Zeng Ping, Liu Yuanliang, Wen Ge, Fu Xiuqiong, Sun Xuegang
The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Int Immunopharmacol. 2015 Jul;27(1):24-31. doi: 10.1016/j.intimp.2015.04.018. Epub 2015 Apr 18.
Increasing evidences showed that the survival of macrophages promotes atherogenesis. Macrophage apoptosis in the early phase of atherosclerotic process negatively regulates the progression of atherosclerotic lesions. We demonstrated that a natural anti-oxidant apigenin could ameliorate atherogenesis in ApoE(-/-) mice. It reduced the number of foam cells and decreased the serum levels of tumor necrosis factor α, interleukin 1β (IL-1β) and IL-6. Our results showed that oxidized low-density lipoprotein (oxLDL) led to the secretion of pro-inflammatory cytokines. Apigenin-induced apoptosis and downregulated the secretion of TNF-α, IL-6 and IL-1β. It is further supported by the use of zVAD, a pan-caspase inhibitor, demonstrating that apigenin lowered cytokine profile through induction of macrophage apoptosis. Moreover, apigenin-induced Atg5/Atg7-dependent autophagy in macrophages pretreated with oxLDL. Results illustrated that autophagy inhibition increased apigenin-induced apoptosis through activation of Bax. The present findings suggest that oxLDL maintained the survival of macrophages and activated the secretion of pro-inflammatory cytokines to initiate atherosclerosis. Apigenin-induced apoptosis of lipid-laden macrophages and resolved inflammation to ameliorate atherosclerosis. In conclusion, combination of apigenin with autophagy inhibition may be a promising strategy to induce foam cell apoptosis and subdue atherogenic cytokines.
越来越多的证据表明巨噬细胞的存活促进动脉粥样硬化的发生。动脉粥样硬化过程早期的巨噬细胞凋亡对动脉粥样硬化病变的进展具有负向调节作用。我们证明了天然抗氧化剂芹菜素可改善载脂蛋白E基因敲除（ApoE(-/-)）小鼠的动脉粥样硬化。它减少了泡沫细胞的数量，并降低了肿瘤坏死因子α、白细胞介素1β（IL-1β）和IL-6的血清水平。我们的结果表明，氧化型低密度脂蛋白（oxLDL）导致促炎细胞因子的分泌。芹菜素诱导细胞凋亡，并下调TNF-α、IL-6和IL-1β的分泌。泛半胱天冬酶抑制剂zVAD的使用进一步支持了这一点，表明芹菜素通过诱导巨噬细胞凋亡降低细胞因子水平。此外，芹菜素在经oxLDL预处理的巨噬细胞中诱导Atg5/Atg7依赖性自噬。结果表明，自噬抑制通过激活Bax增加了芹菜素诱导的细胞凋亡。目前的研究结果表明，oxLDL维持巨噬细胞的存活并激活促炎细胞因子的分泌以启动动脉粥样硬化。芹菜素诱导富含脂质的巨噬细胞凋亡并消除炎症以改善动脉粥样硬化。总之，芹菜素与自噬抑制相结合可能是诱导泡沫细胞凋亡和抑制动脉粥样硬化细胞因子的一种有前景的策略。
