The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, China.
The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
BMC Cardiovasc Disord. 2020 Mar 13;20(1):133. doi: 10.1186/s12872-020-01391-7.
Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process.
Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays.
H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1β, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression.
Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.
先前的研究表明，JAK/STAT 信号通路参与调节动脉外膜炎症反应。在这项研究中，我们设计实验进一步研究 JAK2/STAT3/SOCS3 信号在兔动脉粥样硬化过程中的作用。
通过主动脉球囊损伤联合致动脉粥样硬化饮食诱导兔腹主动脉粥样硬化。同时，在动脉粥样硬化过程中，动物接受或不接受鲁索替尼治疗 12 周。实验期末，处死所有兔子。通过 H&E 染色、油红 O 染色和茜素红染色分别检测腹主动脉斑块面积、斑块脂质负荷和斑块钙负荷。此外，通过生化试剂盒或 ELISA 试剂盒检测兔血浆脂质和炎症细胞因子。最后，通过 RT-qPCR、western blot 和免疫组化检测 JAK2/STAT3/SOCS3 通路相关蛋白的表达和磷酸化水平。
H&E 染色和 CT 扫描分析表明成功构建了兔动脉粥样硬化模型。Janus 激酶 2（JAK2）抑制剂鲁索替尼显著减少高脂饮食和主动脉球囊损伤兔的动脉粥样硬化斑块面积。此外，鲁索替尼显著降低了动脉粥样硬化兔血浆中 IL-6、IL-1β、IFN-γ 和 TNF-α的水平，而增加了 IL-10 和 IL-17 的水平。此外，鲁索替尼降低了动脉粥样硬化兔血浆 TC、TG 和 LDL-C 含量和 AIP 值，同时提高了 HDL-C 水平。此外，我们发现与对照组相比，动脉粥样硬化兔的 JAK2 和 STAT3 磷酸化水平升高，随后由于 JAK2 和 STAT3 的激活，SOCS3 的表达也增加。有趣的是，鲁索替尼可以使 JAK2/STAT3/SOCS3 信号通路失活，降低 SOCS3 表达。
综上所述，抑制 JAK2/STAT3/SOCS3 信号通路可能是临床治疗动脉粥样硬化的一种新方法。
