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(Circulation. 2002;105:1220.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Tumor Necrosis Factor- Regulates Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 Expression in Vascular Smooth Muscle

A. Anwar, MD; A.A. Zahid, MD; K.J. Scheidegger, PhD; M. Brink, PhD; P. Delafontaine, MD

From the Division of Cardiology, University Hospital of Geneva, Switzerland and Division of Cardiovascular Diseases (P.D.), Kansas University Medical Center, Kansas City, Kan.

Correspondence to P. Delafontaine, MD, FACC, Division of Cardiovascular Diseases, Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160-7378. E-mail pdelafontaine{at}kumc.edu

Background— Inflammatory mediators such as tumor necrosis factor- (TNF-), interleukin 1ß (IL-1ß), IL-6, and interferon (IFN-) may change coronary plaque integrity by altering vascular smooth muscle cell (VSMC) survival and modifying the extracellular matrix. Insulin-like growth factor-1 (IGF-1) prevents apoptosis, promotes matrix formation, and can decrease TNF- or IL-1ß–induced proteoglycan degradation.

Methods and Results— To determine the effects of cytokines on the IGF-1 system, rat aortic VSMCs were exposed to TNF- (10 to 500 ng/mL), IL-1ß (20 pg to 10 ng/mL), IL-6 (100 pg to 15 ng/mL), or IFN- (10 to 600 U/mL). IL-1ß, IL-6, and IFN- did not regulate IGF-1, IGF-1 receptor (R), or IGF binding proteins (IGFBPs). However, TNF- markedly decreased IGF-1 mRNA (85% reduction at 24 hours) and increased IGFBP-3 mRNA and protein (300% increase at 24 hours). These changes were blocked by actinomycin D, consistent with a transcriptional mechanism. Experiments using TNF binding protein-1 indicated that these effects were not attributable to secretion of an autocrine factor. Anti–IGFBP-3 antibodies increased VSMC DNA synthesis 3-fold. In addition, apoptosis induced by TNF-, IFN-, and Fas ligand was markedly reduced by desamino-(1-3)-IGF-1.

Conclusions— TNF-, a cytokine that is upregulated in atherosclerotic plaques, reduces IGF-1 and increases IGFBP-3 in VSMCs, likely leading to a reduction in bioactive IGF-1. Because IGF-1 is important for growth and survival of VSMCs, its downregulation by TNF- possibly plays a crucial role in acute and chronic coronary syndromes by decreasing VSMC viability and promoting plaque instability.

Key Words: cells • growth substances • muscle, smooth • apoptosis • atherosclerosis

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