Annexin II inhibition of G protein-regulated inositol trisphosphate formation in rat aortic smooth muscle.
Vasoconstrictor hormones contribute to the pathogenesis of hypertension through intracellular signals that stimulate vascular smooth muscle (VSMC) contraction and/or growth. We previously showed that the glucocorticoid dexamethasone (DEX) inhibited angiotensin II-stimulated inositol trisphosphate (IP3) formation in VSMC, but the mechanism of inhibition is not known. Because glucocorticoids stimulate the expression of annexins and annexin II potently binds phosphoinositides, the role of DEX and annexin II in VSMC G protein-coupled phosphoinositide hydrolysis was investigated. DEX incubation blunted increases in guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S)-stimulated IP3 generation and angiotensin II-induced intracellular Ca2+ mobilization but stimulated elevations in VSMC annexin II content. VSMC incubation with exogenous purified annexin II resulted in concentration-dependent decreases in GTP gamma S-stimulated IP3 formation. In DEX-treated cells, exogenous annexin II did not further diminish GTP gamma S-stimulated IP3 formation, suggesting that endogenous annexin II may be a mediator of DEX-induced inhibition of G protein-coupled IP3 generation. These data represent the first direct evidence of G protein-dependent phosphoinositide hydrolysis regulation by glucocorticoids or annexins. We speculate that annexin II may play a role in the pathogenesis of hypertension through stimulation of VSMC growth.
Schelling
J R
JR
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Gentry
D J
DJ
Dubyak
G R
GR
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017306:Annexin A2 / Q000494:pharmacology* / Q000502:physiology; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism
D017306:Annexin A2; D000804:Angiotensin II; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003907:Dexamethasone; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium