Angiotensin II increases proto-oncogene expression and phosphoinositide turnover in vascular smooth muscle cells via the angiotensin II AT1 receptor.
OBJECTIVE
The aim of this study was to determine which angiotensin II receptor (AT receptor) mediates proto-oncogene expression and phosphoinositide metabolism in vascular smooth muscle cells in vitro.


METHODS
The AT receptor antagonists DuP753 (losartan), an AT1 antagonist, and PD 123319, an AT2 antagonist, were used to characterize AT receptors on cultured vascular smooth muscle cells derived from the rat mesenteric artery and to identify which receptor subtype mediates the angiotensin II-induced increase in proto-oncogene expression and phosphoinositide metabolism.


METHODS
Rat mesenteric artery vascular smooth muscle cells were grown using standard cell culture methods. Proto-oncogene induction was measured using Northern blotting. Phosphoinositide breakdown was assessed by measuring [3H]-inositol phosphates released from prelabelled cells.


RESULTS
Receptor-binding studies revealed that the AT1 receptor predominated on vascular smooth muscle cells. Incubation of quiescent cells with 0.1 mumol/l angiotensin II resulted in a 65% increase in total [3H]-inositol phosphates released compared with unstimulated cells and in a rapid accumulation of c-fos messenger RNA (mRNA). Pre-incubation of the cells with 10(-5) mol/l PD 123319 had no effect on either total inositol phosphates release or c-fos mRNA induction. Both responses, however, were totally abolished by pre-incubation of the cells with 10(-5) mol/l losartan or saralasin.


CONCLUSIONS
Angiotensin II acts through the AT1 receptor to increase c-fos expression and phosphoinositide turnover in vascular smooth muscle cells. These mechanisms may be important in angiotensin II-induced smooth muscle hypertrophy.
Lyall
F
F
MRC Blood Pressure Unit, Western Infirmary, Glasgow, UK.
Dornan
E S
ES
McQueen
J
J
Boswell
F
F
Kelly
M
M
D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D009131:Muscle, Smooth, Vascular / Q000737:chemistry*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011945:Receptors, Angiotensin / Q000032:analysis* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D010716:Phosphatidylinositols; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan