Published Online
on February 18, 2002

A more recent version of this article appeared on March 12, 2002

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Submitted on November 8, 2001
Revised on December 28, 2001
Accepted on January 2, 2002

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, and 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.

^* To whom correspondence should be addressed. 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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