Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit

Abstract

Background: 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.Methods: 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.Results: 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.Conclusion: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

Effect of disease modifying anti-rheumatic drugs on major cardiovascular events: a meta-analysis of randomized controlled trials

“…Due to their powerful anti-inflammatory effects, it is plausible that DMARDs may also prevent cardiovascular events. Inhibition of cytokines, such as tumor necrosis factor (TNF) and interleukins (ILs), and janus kinase (JAK) have been reported to limit inflammatory mechanisms implicated in athero-thrombosis through studies in animal models 10 – 12 . Most commonly prescribed biologic and targeted synthetic DMARDs such as TNF-alpha (α) inhibitors, IL-1 beta (β) & IL-12/23 inhibitors and JAK-1/2 inhibitors have been tested in randomized controlled trials within a variety of different populations that are at risk of MACE, such as people with rheumatoid arthritis and psoriasis 13 – 17 .…”

Anti-Atherogenic Effects of Orlistat on Obesity-Induced Vascular Oxidative Stress Rat Model

“…The previous study has shown that TNF-ɑ is a key pro-inflammatory marker, which also upregulates the VCAM-1 and ICAM-1 expressions and stimulates the adherence of monocytes to the endothelial surface [57]. The TNF-ɑ is primarily secreted by macrophages and further triggers the release of more inflammatory cytokines such as IL-1β, IFN-γ, and IL-6 [58]. We observed significant increases in the expressions of pro-inflammatory marker of TNF-ɑ and adhesion molecules VCAM-1 and ICAM-1, with simultaneous decrease in the expression of anti-inflammatory marker of IL-10 in the OB group.…”

Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review

“…Wolach and collaborators [66] demonstrated that, in a deep-vein-stenosis murine model, NET formation and thrombosis are blunted by inhibition of Jak2 with ruxolitinib. In a very recent study in rabbits fed a high-fat diet, ruxolitinib reduced the atherosclerosis induced in aorta by balloon injury [86]. Furthermore, it has been shown that the selective Jak2 inhibition with fedratinib reduces the formation of atherosclerotic plaque in Apoe-/-mice [87].…”