Evidence for an age-related dysfunction in the antiproliferative response to transforming growth factor-beta in vascular smooth muscle cells.
Open Access
- 1 March 1993
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 4 (3), 315-322
- https://doi.org/10.1091/mbc.4.3.315
Abstract
Previous studies have indicated that aged animals show an increased intimal hyperplasia after arterial injury. The present studies examined the hypothesis that the increased serum-free proliferation of aged smooth muscle cells (SMC), in vitro, was due to a loss of an antiproliferative signal, such as transforming growth factor-beta 1 (TGF-beta 1). Northern blot analysis of the mRNA derived from old (> 19 mo) or young (3-4 mo) rat aortic SMC indicated that both groups had an equivalent level of the 2.5 kB TGF-beta 1 message. Metabolic labeling with 35S-methionine and immunoprecipitation for TGF-beta 1 confirmed the de novo synthesis of TGF-beta 1 in rat SMC. Old and young SMC supernatants showed equal levels of active or latent (acid-activated) TGF-beta activity. Despite the similarities in the production of TGF-beta 1, old SMC were refractory to inhibition by TGF-beta 1, whereas young SMC were markedly inhibited (80%) by low levels of TGF-beta 1 (IC50 < 5 pg/ml). Binding studies at 4 degrees C indicated that old SMC exhibited reduced binding capacity for 125I-TGF-beta 1. Cross-linking studies confirmed that old SMC showed reduced binding of 125I-TGF-beta 1 to membrane sites corresponding to the high molecular weight type III receptor, as well as the 85-kDa type II and 65-kDa type I receptor. However, at 37 degrees C, old SMC degraded 125I-TGF-beta 1 more rapidly than young SMC. Combined, this data suggests that SMC derived from older animals are capable of normal production of TGF-beta 1 but fail to respond to the autocrine growth inhibitory effects of this agent, thereby leading to enhanced proliferation.Keywords
This publication has 32 references indexed in Scilit:
- Cell Type and Cell State Specific Antibodies in the Analysis of Early Lesions of Human AtherosclerosisAmerican Journal of Hypertension, 1992
- Fucoidan is a non-anticoagulant inhibitor of intimal hyperplasiaBiochemical and Biophysical Research Communications, 1992
- Expression cloning of the TGF-β type II receptor, a functional transmembrane serine/threonine kinaseCell, 1992
- Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor systemCell, 1991
- Aging and atherosclerosis in the rabbitAtherosclerosis, 1991
- Concomitant loss of transforming growth factor (TGF)-beta receptor types I and II in TGF-beta-resistant cell mutants implicates both receptor types in signal transduction.Journal of Biological Chemistry, 1990
- Latent Forms of TGF‐β: Structure and BiologyAnnals of the New York Academy of Sciences, 1990
- Inhibition of mink lung epithelial cell proliferation by transforming growth factor-β is coupled through a pertussis-toxin-sensitive substrateBiochemical Journal, 1990
- Transforming growth factor-β receptors and binding proteoglycansJournal of Cell Science, 1990
- Growth characteristics and cytoskeletal organization of cultured smooth muscle cells from human primary stenosing and restenosing lesions.Arteriosclerosis: An Official Journal of the American Heart Association, Inc., 1990