Induction of a hypertrophic growth status of coronary smooth muscle cells is associated with an overexpression of TGF-beta.
Hypertrophy of vascular smooth muscle cells occurs during hypertension-induced remodelling of arteries and during development of arteriosclerosis and restenosis following angioplasty but the pathogenesis of the hypertrophic status is not yet fully understood. In a previous study we demonstrated that the synthetic non-sulfated, non-toxic heparin-mimicking compound RG-13577 is capable of inducing a cell cycle-arrested hypertrophic phenotype of coronary smooth muscle cells. In this study we clarify the mode of action of RG-13577 and demonstrate that the RG-13577-induced hypertrophy is associated with an increased expression of TGF-beta1 as indicated by an increase in TGF-beta1-specific protein and mRNA level. Furthermore we show that RG-13577-treated hypertrophic smooth muscle cells maintain full metabolic activity as indicated by a continuous de novo synthesis of protein and proteoglycans and that the RG-13577-induced growth arrest is caused not only by a higher expression of TGF-beta, but also by a reduced response of RG-treated cells to the mitogenic activity of bFGF, PDGF and EGF. The growth inhibitory activity of RG-13577 is reduced in the presence of neutralizing antibodies against TGF-beta. TGF-beta itself has anti-proliferative activity in serum-depleted medium. The RG-13577 effect is reversible since incubation of hypertrophic cells in RG-13577-free medium restores cell volume and [3H]thymidine incorporation to the values of untreated control cells within 4 days. We conclude, that the active metabolic status of RG-13577-treated cells in association with the overexpression of TGF-beta could promote repair processes of injured arteries after angioplasty without stimulating cell proliferation.
Schmidt
Annette
A
Institute for Arteriosclerosis Research, Division of Molecular Cardiology, University of Münster, Germany. annschm@uni-muenster.de
Göpfert
Christian
C
Vlodavsky
Israel
I
Völker
Wolfgang
W
Buddecke
Eckhart
E
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D006131:Growth Inhibitors / Q000494:pharmacology; D006984:Hypertrophy; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D010642:Phenoxyacetates / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers / Q000378:metabolism / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D006131:Growth Inhibitors; D010642:Phenoxyacetates; D011108:Polymers; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; C090697:2-(4-hydroxyphenoxy)acetic acid-formaldehyde polymer