Angiotensin II regulates tenascin gene expression in vascular smooth muscle cells.
Angiotensin II, a vasoactive peptide, has been implicated in the pathophysiology of a number of vascular wall abnormalities. Since aberrant extracellular matrix deposition contributes to the pathogenesis of vessel wall disease, we examined the potential involvement of angiotensin II in the regulation of extracellular matrix synthesis by vascular smooth muscle cells. Immunoprecipitation of newly synthesized matrix proteins showed that, under serum-free conditions, cultured vascular smooth muscle cells constitutively produced high levels of fibronectin, small amounts of laminin, and a barely detectable amount of tenascin. Angiotensin II treatment increased synthesis of a 230-kDa tenascin glycoprotein by 9-fold and fibronectin synthesis by only 30-40% during a 24-h treatment period, without stimulating laminin production or a general increase in the synthesis of secreted proteins. Concomitant treatment with saralasin, a competitive inhibitor of angiotensin II, prevented the stimulation observed with angiotensin II. The stimulation of immunoprecipitable tenascin was preceded by an increase in tenascin mRNA. Levels of tenascin transcripts (8.4 and 7.0 kilobase) were significantly increased within 2 h after angiotensin II treatment, reached a maximum (10- to 12-fold) by 4 h, and remained elevated after 18 h. The induction was completely blocked by actinomycin D. Serum also induced tenascin mRNA, but with a different time course. Serum induction of tenascin mRNA was also evident at 2 h, maximal at 4 h, but declined to control levels at 8 h. These results indicate that angiotensin II exerts a rapid and selective stimulation of tenascin biosynthesis, at least in part at a transcriptional level. This suggests that angiotensin II may alter the composition of the extracellular matrix of the vessel wall by stimulating synthesis of the antiadhesive protein tenascin.
Sharifi
B G
BG
Division of Cardiology, Cedars-Sinai Medical Center, UCLA School of Medicine 90048.
LaFleur
D W
DW
Pirola
C J
CJ
Forrester
J S
JS
Fagin
J A
JA
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015152:Blotting, Northern; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015342:DNA Probes; D003609:Dactinomycin / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D007700:Kinetics; D007797:Laminin / Q000096:biosynthesis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019063:Tenascin
D015816:Cell Adhesion Molecules, Neuronal; D015342:DNA Probes; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007797:Laminin; D012333:RNA, Messenger; D019063:Tenascin; D000804:Angiotensin II; D003609:Dactinomycin; D012313:RNA; D003513:Cycloheximide