Elastase enhances cAMP accumulation and the inhibition of DNA synthesis induced by OP-41483, a stable prostacyclin analogue, in vascular smooth muscle cells.
To define the physiological roles of elastase in the vascular wall, we examined whether elastase at low concentrations can modulate the proliferation of vascular smooth muscle cells (VSMC). Elastase itself at low concentrations from 1 to 50 ng/ml inhibited DNA synthesis dose-dependently in VSMC. However, phenylmethylsulfonyl fluoride-inactivated elastase failed to induce this inhibition. OP-41483, a stable analogue of prostacyclin, inhibited DNA synthesis and stimulated accumulation of cAMP in VSMC. Preincubation of VSMC for 24 h with 50 ng/ml elastase enhanced both inhibition of DNA synthesis and the accumulation of cAMP induced by OP-41483. Preincubation of VSMC with 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C (PKC), also enhanced cAMP accumulation induced by OP-41483. On the other hand, elastase failed to enhance OP-41483-induced cAMP accumulation in PKC down-regulated cells. Furthermore, coincubation with chelerythrine, an inhibitor of PKC, inhibited the enhancement of cAMP accumulation induced by preincubation with elastase. These results suggest that elastase at low concentrations can enhance the inhibition of VSMC proliferation induced by prostacyclin through the activation of protein kinase C.
Fukuo
K
K
Department of Geriatric Medicine, Osaka University Medical School, Japan.
Morimoto
S
S
Jiang
B
B
Inoue
T
T
Nabata
T
T
Ogihara
T
T
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010196:Pancreatic Elastase / Q000502:physiology*; D051381:Rats; D047391:alpha-Cyclodextrins
D003505:Cyclodextrins; D047391:alpha-Cyclodextrins; C051518:OP 41483-alpha-cyclodextrin; D004247:DNA; D011464:Epoprostenol; D000242:Cyclic AMP; D010196:Pancreatic Elastase