Gene delivery of suppressors of cytokine signaling (SOCS) inhibits inflammation and atherosclerosis development in mice

Abstract

Chronic activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway contributes to vascular inflammation and atherosclerosis by inducing expression of genes involved in cell proliferation, differentiation and migration. We aimed to investigate whether enforced expression of negative regulators, the suppressors of cytokine signaling (SOCS1 and SOCS3), inhibits harmful JAK/STAT-mediated responses and affects atherosclerosis in apolipoprotein E knockout mice. Adenovirus-mediated SOCS1 transgene expression impaired the onset and progression of atherosclerosis without impact on lipid profile, whereas SOCS3 was only effective on early atherosclerosis. Mechanistically, SOCS gene delivery, primarily SOCS1, attenuated STAT1 and STAT3 activation and reduced the expression of STAT-dependent genes (chemokine/chemokine receptors, adhesion molecules, pro-inflammatory cytokines and scavenger receptors) in aortic tissue. Furthermore, atherosclerotic plaques exhibit a more stable phenotype characterized by lower lipids, T cells and M1 macrophages and higher M2 macrophages and collagen. Atheroprotection was accompanied by a systemic alteration of T helper- and T regulatory-related genes and a reduced activation state of circulating monocytes. In vascular smooth muscle cells and macrophages, SOCS gene delivery inhibited cytokine-induced STAT activation, pro-inflammatory gene expression, cell migration and proliferation. In conclusion, targeting SOCS proteins, predominantly SOCS1, to suppress pathological mechanisms involved in atheroma plaque progression and destabilization could be an interesting anti-atherosclerotic strategy.

TWEAK blockade decreases atherosclerotic lesion size and progression through suppression of STAT1 signaling in diabetic mice

“…JAK/STAT is also a key inflammatory mechanism by which hyperglycemia contributes to the diabetic complications1820. Targeting JAK/STAT activation inhibits proinflammatory genes expression, leukocyte infiltration, and vascular cell activation, thereby preventing development and progression of atherosclerosis in diabetic mice2041. The inflammatory response induced by JAK/STAT pathway comprises different genes including chemokines, cytokines, enzymes and vasoactive proteins, many of them upregulated by diabetic conditions19.…”

Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome

“…Altering the SOCS1/SOCS3 balance or the activity of these negative regulators would be an attractive therapeutic approach and is under investigation (96). A therapeutic SOCS1 KIR mimetic peptide has shown great promise in preventing the development of multiple sclerosis in a mouse experimental autoimmune encephalomyelitis model and even ameliorates clinical symptoms of lupus in a rodent model (97).…”

Protein Inhibitor of Activated STAT3 Suppresses Oxidized LDL-induced Cell Responses during Atherosclerosis in Apolipoprotein E-deficient Mice

“…Previous studies have shown that SOCS1 and SOCS3 are closely correlated with atherosclerosis progression151617. However, they appear to have different expression patterns and play opposing roles during atherogenesis173233.…”

“…To avoid excessive inflammation in vivo , some protein inhibitors, such as suppressor of cytokine signalling (SOCS), protein inhibitor of activated STAT (PIAS) and protein tyrosine phosphatases, are involved in negatively regulating JAK/STAT signalling activation14. The findings of previous studies indicate that SOCS1 and SOCS3 are closely correlated with atherosclerosis progression151617. High SOCS1 and SOCS3 expression levels were detected in VSMCs and macrophages in both human atherosclerotic plaques and apolipoprotein E knockout (ApoE −/− ) mouse aortic lesions.…”