Chao Meng-Lin, Guo Junhong, Cheng Wen-Lin, Zhu Xue-Yong, She Zhi-Gang, Huang Zan, Ji Yong, Li Hongliang
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
The Institute of Model Animals of Wuhan University, Wuhan, China.
J Am Heart Assoc. 2016 Dec 22;5(12):e004362. doi: 10.1161/JAHA.116.004362.
Atherosclerosis is a chronic disease that is closely related to inflammation and macrophage apoptosis, which leads to secondary necrosis and proinflammatory responses in advanced lesions. Caspase-activated DNase (CAD) is a double-strand specific endonuclease that leads to the subsequent degradation of chromosome DNA during apoptosis. However, whether CAD is involved in the progression of atherosclerosis remains elusive.
CADApoE and ApoE littermates were fed a high-fat diet for 28 weeks to develop atherosclerosis. Human specimens were collected from coronary heart disease (CHD) patients who were not suitable for transplantation. CAD expression was increased in the atheromatous lesions of CHD patients and high-fat diet-treated ApoE-deficient mice. Further investigation demonstrated that CAD deficiency inhibited high-fat diet-induced atherosclerosis, as evidenced by decreased atherosclerotic plaques, inhibited inflammatory response, and macrophage apoptosis, as well as enhanced stability of plaques in CADApoE mice compared to the ApoE controls. Bone marrow transplantation verified the effect of CAD on atherosclerosis from macrophages. Mechanically, the decrease in the phosphorylated levels of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-regulated kinase 1 and 2 (MEK-ERK1/2) that resulted from CAD knockout and the activation of nuclear factor kappa B signaling mediated by CAD stimulation that was suppressed by inhibiting ERK1/2 phosphorylation revealed the potential association between the role of CAD in atherosclerosis and the MAPK signaling pathway.
In conclusion, CAD deficiency protects against atherosclerosis through inhibiting inflammation and macrophage apoptosis, which is partially through inactivation of the MEK-ERK1/2 signaling pathway. This finding provides a promising therapeutic target for treating atherosclerosis.
动脉粥样硬化是一种与炎症和巨噬细胞凋亡密切相关的慢性疾病，在晚期病变中会导致继发性坏死和促炎反应。半胱天冬酶激活的脱氧核糖核酸酶（CAD）是一种双链特异性核酸内切酶，在细胞凋亡过程中会导致染色体DNA的后续降解。然而，CAD是否参与动脉粥样硬化的进展仍不清楚。
将CAD基因敲除的载脂蛋白E（ApoE）小鼠和野生型ApoE同窝小鼠喂食高脂饮食28周以诱导动脉粥样硬化。从不适于移植的冠心病（CHD）患者中收集人体标本。CAD在CHD患者的动脉粥样硬化病变以及高脂饮食处理的ApoE基因敲除小鼠中表达增加。进一步研究表明，CAD缺乏可抑制高脂饮食诱导的动脉粥样硬化，表现为动脉粥样硬化斑块减少、炎症反应和巨噬细胞凋亡受到抑制，与ApoE对照相比，CAD基因敲除的ApoE小鼠的斑块稳定性增强。骨髓移植证实了CAD对巨噬细胞所致动脉粥样硬化的影响。机制上，CAD基因敲除导致的丝裂原活化蛋白激酶（MAPK）激酶/细胞外信号调节激酶1和2（MEK-ERK1/2）磷酸化水平降低，以及CAD刺激介导的核因子κB信号通路的激活被ERK1/2磷酸化抑制所抑制，揭示了CAD在动脉粥样硬化中的作用与MAPK信号通路之间的潜在关联。
总之，CAD缺乏通过抑制炎症和巨噬细胞凋亡来预防动脉粥样硬化，部分是通过使MEK-ERK1/2信号通路失活。这一发现为治疗动脉粥样硬化提供了一个有前景的治疗靶点。
