Published online before print January 22, 2009, doi: 10.1161/ATVBAHA.108.173781
© 2009 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis
From Renal and Vascular Inflammation (G.O.-M., P.H.-V., B.M., V.L.-P., P.F.-V., C.G.-G.) and the Vascular Research Laboratory (J.L.M.-V., B.M.-G., J.E.), Fundacion Jimenez Diaz, Autonoma University; and the Biochemistry Department (O.L.-F.) and Hospital Clinico San Carlos (L.O.), Complutense University, Madrid, Spain.
Correspondence to Carmen Gomez-Guerrero, PhD, Renal and Vascular Inflammation Lab, Fundacion Jimenez Diaz (Autonoma University), Avda. Reyes Catolicos, 2 Madrid 28040, Spain. E-mail cgomez{at}fjd.es
Objective— Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development.
Methods and Results— Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area. SOCS were also increased in aortic lesions from apoE–/– mice. In cultured VSMCs, endothelial cells, and monocytes, SOCS1 and SOCS3 were transiently induced by proinflammatory cytokines, proatherogenic lipoproteins, and immune molecules. Furthermore, overexpression of SOCS suppressed STAT activation and reduced inflammatory gene expression and cell growth, whereas SOCS knockdown increased these cell responses. In vivo, antisense oligodeoxynucleotides targeting SOCS3 exacerbated the atherosclerotic process in apoE–/– mice by increasing the size, leukocyte content, and chemokine expression in the lesions.
Conclusions— SOCS expressed in atherosclerotic lesions are key regulators of vascular cell responses. Activation of this endogenous antiinflammatory pathway might be of interest in the treatment of atherosclerosis.
We demonstrated an increased expression of SOCS proteins in human and experimental atherosclerotic plaques. In vitro, STAT activation, gene expression, and cell growth were prevented by SOCS overexpression and were increased by SOCS downregulation. In vivo, antisense oligonucleotides targeting SOCS aggravated the atherosclerotic process. This suggests an important role of SOCS as negative regulators of inflammation during atherosclerosis.
Key Words: atherosclerosis • inflammation • signal transduction • proliferation • chemokines
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