Heparin/endothelial cell growth supplement regulates matrix gene expression and prolongs life span of vascular smooth muscle cells through modulationof interleukin-1

Vascular smooth muscle cells produce and respond to interleukin-1, a cytoki ne which modifies inflammation-associated vascular activities including the synthesis of extracellular matrix proteins. We have established vascular s mooth muscle cells culture conditions in which heparin, in the presence of endothelial cell growth supplement, promotes cell proliferation and inhibit s interleukin-1 and matrix protein expression. To test whether interleukin- 1 mediates growth and matrix modulation by heparin/endothelial cell growth supplement, vascular smooth muscle cells were transfected with an Epstein-B arr virus-derived expression vector designed to express interleukin-1 antis ense transcripts. RNase protection and ELISA assays demonstrated a complete block of interleukin-1 transcription and protein synthesis. Northern blot analysis also showed that interleukin-1 antisense decreased the expression of matrix genes such as type I collagen, fibronectin, and decorin similar t o downregulation after heparin/endothelial cell growth supplement treatment . In contrast, the expression of versican was not affected, indicating a se lective suppression of matrix proteins. In addition, interleukin-1 antisens e significantly prolonged the life span of vascular smooth muscle cells in culture. Our data suggest that heparin/endothelial cell growth supplement i nduces matrix remodeling and controls growth and senescence of vascular smo oth muscle cells through down-regulation of interleukin-1.