Carlota Recio1, Ainhoa Oguiza1, Iolanda Lazaro1, Beñat Mallavia1, Jesus Egido1, Carmen Gomez-Guerrero2. 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.
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.
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 diabeticmice and identified the mechanisms involved. APPROACH AND RESULTS:Streptozotocin-induced diabetic apolipoprotein E-deficientmice (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 diabeticmice 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 diabeticmice, 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: Sara La Manna; Laura Lopez-Sanz; Flavia Anna Mercurio; Sara Fortuna; Marilisa Leone; Carmen Gomez-Guerrero; Daniela Marasco Journal: ACS Med Chem Lett Date: 2020-03-19 Impact factor: 4.345
Authors: Z X Zhong; B Li; C R Li; Q F Zhang; Z D Liu; P F Zhang; X F Gu; H Luo; M J Li; H S Luo; G H Ye; F L Wen Journal: Braz J Med Biol Res Date: 2014-11-21 Impact factor: 2.590