title: 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.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Renal and Vascular Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain (C.R., A.O., I.L., B.M., J.E., C.G.-G.); and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain (C.R., A.O., J.E., C.G.-G.).
authors.forename: Carlota
authors.initials: C
authors.lastname: Recio
authors.affiliation: From the Renal and Vascular Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain (C.R., A.O., I.L., B.M., J.E., C.G.-G.); and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain (C.R., A.O., J.E., C.G.-G.).
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Oguiza
authors.affiliation: From the Renal and Vascular Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain (C.R., A.O., I.L., B.M., J.E., C.G.-G.); and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain (C.R., A.O., J.E., C.G.-G.).
authors.forename: Iolanda
authors.initials: I
authors.lastname: Lazaro
authors.affiliation: From the Renal and Vascular Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain (C.R., A.O., I.L., B.M., J.E., C.G.-G.); and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain (C.R., A.O., J.E., C.G.-G.).
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.affiliation: From the Renal and Vascular Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain (C.R., A.O., I.L., B.M., J.E., C.G.-G.); and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain (C.R., A.O., J.E., C.G.-G.).
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: From the Renal and Vascular Research Lab, IIS-Fundacion Jimenez Diaz, Autonoma University of Madrid, Madrid, Spain (C.R., A.O., I.L., B.M., J.E., C.G.-G.); and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain (C.R., A.O., J.E., C.G.-G.). cgomez@fjd.es c.gomez@uam.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002942:Circular Dichroism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D015850:Interleukin-6; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D053612:Janus Kinases
keywords: atherosclerosis; cytokines; lipopeptides