Insulin-like growth factor binding protein-4 expression is decreased by angiotensin II and thrombin in rat aortic vascular smooth muscle cells.
Insulin-like growth factor-I (IGF-I) is a ubiquitous peptide that regulates cellular growth and differentiation and is involved in vascular proliferative responses. The effects of IGF-I are modulated by several IGF-I binding proteins (IGFBPs), including IGFBP-4, the main IGFBP produced by vascular smooth muscle cells (VSMCs). We have previously shown that angiotensin II (Ang II)-induced and thrombin-induced mitogenesis in VSMCs is dependent on autocrine IGF-I. In addition, we have demonstrated that IGF-I and IGFBP-4 mRNA levels are upregulated in the hypertensive aorta of abdominally coarcted rats, a high-renin hypertension model. To obtain further insight into the IGF-I system and to specifically study changes in IGFBP-4, a known inhibitor of IGF-I action, VSMCs were incubated with Ang II or thrombin. Compared with control, Ang II induced an 87+/-2% downregulation of IGFBP-4 mRNA levels at 24 hours, with a 61+/-6% decrease of IGFBP-4 levels, as determined by Western ligand blot analysis. Thrombin had the same depressor effects (87+/-2% for the mRNA levels and 61+/-3% for the protein levels). Ang II and thrombin coincubation with (125)I-IGFBP-4 in the conditioned media failed to reveal any increase in fragmentation, indicating that proteolytic cleavage of IGFBP-4 was not involved in the observed effects. Exogenous recombinant human IGFBP-4 decreased thrombin-induced DNA synthesis of human aortic VSMCs by 64%, whereas anti-IGFBP-4 antibody potentiated thrombin-induced DNA synthesis. These data suggest that downregulation of IGFBP-4 expression in VSMCs may play a critical role in vascular growth response to Ang II and thrombin in normal and diseased states, by increasing the bioavailability of IGF-I for its cell-surface receptor.
Anwar
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A
Hôpital Cantonal Universitaire de Genève, Geneva, Switzerland. Asif.Anwar@hcuge.ch
Zahid
A A
AA
Phillips
L
L
Delafontaine
P
P
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003609:Dactinomycin / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D017077:Culture Media, Conditioned; D018974:Insulin-Like Growth Factor Binding Protein 4; D018969:Insulin-Like Growth Factor Binding Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000804:Angiotensin II; D003609:Dactinomycin; D010450:Endopeptidases; D013917:Thrombin; D013936:Thymidine