REGULATION OF THROMBOSPONDIN-1 PRODUCTION BY ANGIOTENSIN-II IN RAT-HEART ENDOTHELIAL-CELLS

Thrombospondin-l (TSP-1) is synthesized, secreted, and incorporated in to the extracellular matrix by a variety of cells, including the endot helial cells. Addition of angiotensin Il (AII) significantly induced T SP-1 mRNA in rat heart-derived endothelial cells. TSP-1 mRNA levels re ached a plateau within 2 h after the addition of AII and decreased aft er 5 h. The induction was superinduced by cycloheximide and blocked by actinomycin D. Losartan, an AT1 receptor antagonist, could abolish th e induction of TSP-1 mRNA by AII. Phorbol 12-myristate 13-acetate (TPA ) was found to enhance TSP-1 mRNA level whereas a protein kinase C inh ibitor, H7, was shown to block the induction. Immunoblot analysis reve aled that TSP-1 was detectable in the medium 4 h after AII stimulation . Our results suggest that the upregulation of TSP-1 by AII represents an important mechanism leading to perivascular fibrosis in the heart.