Abstract
BackgroundPrevious 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.MethodsAtherosclerosis 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.ResultsH&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.ConclusionTaken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.
Highlights
Previous studies have indicated that the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signaling pathway is involved in modulating arterial adventitia inflammation response
Establishment of rabbit atherosclerosis model To verify whether the rabbit atherosclerosis model was constructed successfully, rabbit atherosclerotic plaques were detected by H&E staining, CT scan analysis, Oil Red O and Alizarin Red S staining
Ruxolitinib alleviated atherosclerosis progress in rabbits It has reported that the JAK/STAT signaling pathway is important in atherosclerotic lesion development [7, 9, 16], so we explored the function of ruxolitinib, an inhibitor of Janus kinase 2 (JAK2), in atherosclerosis progress of rabbits
Summary
Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. We designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process. Atherosclerosis, a complex cardiovascular disease, has been reported as a chronic inflammatory disease by the increasing studies [1, 2]. As reported in previous studies, in the process of atherosclerotic lesion development Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway play a key role [7,8,9]. Yang et al BMC Cardiovascular Disorders (2020) 20:133 pathway and exert profound actions in regulating immunity and inflammation [10]. Whether ruxolitinib plays a key role in atherosclerosis process and JAK2/STAT3/SOCS3 signaling pathway is still not well understood
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