Abstract
We employed des-Arg9-bradykinin to investigate the relation between bradykinin-induced prostaglandin (PG) synthesis and bradykinin-induced protein accumulation. In this feedback control system, bradykinin-induced PG synthesis limits bradykinin-induced protein production. At low concentration (5 X 10(-8) M), des-Arg9-bradykinin was significantly less active than bradykinin in stimulating the formation of prostaglandins by human fetal lung fibroblasts in culture. At high concentration (5 X 10(-6) M), bradykinin induced a 24% increase in protein formation, while des-Arg9-bradykinin induced a 61% increase in collagen formation and an 80% increase in total protein accumulation. In the presence of indomethacin, bradykinin-induced protein formation was increased further, whereas des-Arg9-bradykinin-induced protein formation was unchanged. The bradykinin derivative increased the production of types I and III procollagens without affecting the distribution of procollagen types. The incorporation of [3H]thymidine into DNA in lung fibroblast cultures was increased 3-fold by des-Arg9-bradykinin alone or by bradykinin in combination with indomethacin. Des-Arg9-[Leu8]bradykinin inhibited the des-Arg9-bradykinin-induced protein formation and cell division. These data indicate that both bradykinin and des-Arg9-bradykinin stimulate protein formation and cell division; des-Arg9-bradykinin alone stimulates protein formation and cell division without activating PG synthesis and PG feedback control.
Highlights
(PG) synthesis and bradykinin-induced protein accu- increase inproteinformation induced by bradykinin was mulation
C-terminal arginine residue results in the formation of the biologically active metabolite des-A&-bradykinin (4,5 ). This metabolite is less active than bradykinin in stimulating PG synthesis by endothelial cells in culture [6], certain vparsocu-lar tissues appear to have surface receptors which are tein formation was increasedfurther,whereas des- activated by exposure to des-Argg-bradykinin (4, Arg”-bradykinin-inducedproteinformation was un- 5 )
The bradykinidnerivative increased the pro- than bradykinin in stimulating PG synthesis by lung fibroduction of types I and 111procollagens withoutaffect- blasts in culture; this bradykinin derivative dramating the distribution of procollagen types
Summary
After the pulse-labeling period,a solution of protease inhibitors was line (collagen) and nondialyzable ['4C]proline (total protein) by lung fibroblasts in culture (Fig. 1) In these studies, bradykinin (5 X M)stimulated a 24%increase in total protein production but induced no change icnollagen production. Toensurethat des-Argg-bradykinin-inducedincrease in cent fibroblasts were maintained in medium containing 0.4%serum [14C]hydroxyproline reflected an increase incollagen formafor 2 days. These cultures were labeled with [3H]arachidonic acid (specific activity, 867.4 Ci/mmol; New England Nuclear). The culture mediumwasreplacedwith serum-free medium Bradykininanddes-Ar2-bradykinin were examinedfor containing 0.1 pCi/ml of [~nethyl-~HIthymidin(sepecific activity, their effects on cell division.
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