Suppressors of Cytokine Signaling Modulate JAK/STAT-Mediated Cell Responses During Atherosclerosis

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.