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

Carlota Recio; Ainhoa Oguiza; Iolanda Lazaro; Beñat Mallavia; Jesus Egido; Carmen Gomez-Guerrero

doi:10.1161/ATVBAHA.114.304144

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

Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1953-60. doi: 10.1161/ATVBAHA.114.304144. Epub 2014 Jul 10.

Authors

Carlota Recio¹, Ainhoa Oguiza¹, Iolanda Lazaro¹, Beñat Mallavia¹, Jesus Egido¹, Carmen Gomez-Guerrero²

Affiliations

¹ 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.).
² 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.

PMID: 25012131
DOI: 10.1161/ATVBAHA.114.304144

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.

Approach and 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.

Keywords: atherosclerosis; cytokines; lipopeptides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Cell Line
Circular Dichroism
Diabetes Mellitus, Experimental / complications*
Diabetes Mellitus, Experimental / metabolism
Disease Progression
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
Inflammation / drug therapy*
Inflammation / enzymology
Inflammation / etiology
Interferon-gamma / pharmacology
Interleukin-6 / pharmacology
Janus Kinases / antagonists & inhibitors*
Macrophages / drug effects
Macrophages / metabolism
Mice
Molecular Sequence Data
Molecular Targeted Therapy
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
Peptide Fragments / chemistry
Peptide Fragments / pharmacology
Peptide Fragments / therapeutic use
Plaque, Atherosclerotic / drug therapy*
Plaque, Atherosclerotic / enzymology
Plaque, Atherosclerotic / etiology
Protein Conformation
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
STAT1 Transcription Factor / antagonists & inhibitors*
STAT1 Transcription Factor / physiology
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / physiology
Signal Transduction / drug effects*
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins / chemistry
Suppressor of Cytokine Signaling Proteins / pharmacokinetics
Suppressor of Cytokine Signaling Proteins / pharmacology
Suppressor of Cytokine Signaling Proteins / therapeutic use*

Substances

Interleukin-6
Peptide Fragments
Protein Kinase Inhibitors
STAT1 Transcription Factor
STAT3 Transcription Factor
Socs1 protein, mouse
Stat1 protein, mouse
Stat3 protein, mouse
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins
Interferon-gamma
Janus Kinases