Suppressor of cytokine signaling 1-derived peptide inhibits Janus kinase/signal transducers and activators of transcription pathway and improves inflammation and atherosclerosis in diabetic mice.

Activation of Janus kinase/signal transducers and activators of transcription (STAT) pathway by hyperglycemia and dislypidemia contributes to the progression of diabetic complications, including atherosclerosis. Suppressor of cytokine signaling (SOCS) proteins negatively regulate Janus kinase/STAT and have emerged as promising target for anti-inflammatory therapies. We investigated whether a cell-permeable lipopeptide corresponding to the kinase inhibitory region of SOCS1 could reduce atherosclerosis in diabetic mice and identified the mechanisms involved. Streptozotocin-induced diabetic apolipoprotein E-deficient mice (aged 8 and 22 weeks) were given intraperitoneal injections of vehicle, SOCS1-derived peptide, or control mutant peptide for 6 to 10 weeks. SOCS1 therapy suppressed STAT1/STAT3 activation in atherosclerotic plaques of diabetic mice and significantly reduced lesion size at both early and advanced stages of lesion development compared with vehicle group. Plaque characterization demonstrated that SOCS1 peptide decreased the accumulation of lipids, macrophages, and T lymphocytes, whereas increasing collagen and smooth muscle cell content. This atheroprotective effect was accompanied by systemic (reduced proinflammatory Ly6C(high) monocytes and splenic cytokine expression) and local (reduced aortic expression of chemokines and cytokines) mechanisms, without impact on metabolic parameters. In vitro, SOCS1 peptide dose dependently inhibited STAT1/STAT3 activation and target gene expression in vascular smooth muscle cells and macrophages and also suppressed cytokine-induced cell migration and adhesion processes. SOCS1-based targeting Janus kinase/STAT restrains key mechanisms of atherogenesis in diabetic mice, thereby preventing plaque formation and increasing plaque stability. Approaches to mimic native SOCS1 functions may have a therapeutic potential to retard the progression of diabetic complications.

Recio C ，Oguiza A ，Lazaro I ，Mallavia B ，Egido J ，Gomez-Guerrero C ... -  《-》

Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis.

Ortiz-Muñoz G ，Martin-Ventura JL ，Hernandez-Vargas P ，Mallavia B ，Lopez-Parra V ，Lopez-Franco O ，Muñoz-Garcia B ，Fernandez-Vizarra P ，Ortega L ，Egido J ，Gomez-Guerrero C ... -  《-》

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

Recio C ，Oguiza A ，Mallavia B ，Lazaro I ，Ortiz-Muñoz G ，Lopez-Franco O ，Egido J ，Gomez-Guerrero C ... -  《-》

Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes.

Norkina O ，Dolganiuc A ，Catalano D ，Kodys K ，Mandrekar P ，Syed A ，Efros M ，Szabo G ... -  《-》

Both the suppressor of cytokine signaling 1 (SOCS-1) kinase inhibitory region and SOCS-1 mimetic bind to JAK2 autophosphorylation site: implications for the development of a SOCS-1 antagonist.

Waiboci LW ，Ahmed CM ，Mujtaba MG ，Flowers LO ，Martin JP ，Haider MI ，Johnson HM ... -  《JOURNAL OF IMMUNOLOGY》