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Mitogenic activity of endothelin on human cultured prostatic smooth muscle cells
1Institute for Drug Discovery Research, Yamanouchi Pharmaceutical, Tsukuba, Ibaraki, Japan. saita@yamanouchi.co.jp
Abstract:
The effects of endothelins on human prostatic smooth-muscle cell growth were examined. Endothelin-1 and endothelin-3 induced a concentration-dependent increase in DNA synthesis and also promoted cell growth. Use of subtype selective antagonists BQ-123 ((cyclo(D-Trp-D-Asp(ONa)-Pro-D-Val-Leu); endothelin ET(A) receptor selective) and BQ-788 ((N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl Leu-D-Trp-(COOMe)-D-Nle-ONa); endothelin ET(B) receptor selective), indicated that mitogenic effects of endothelin were mediated through activation of both endothelin ET(A) and ET(B) receptors. The mitogenic effects of endothelin-1 and endothelin-3 were significantly inhibited by pretreatment of the cells with pertussis toxin. However, mitogenesis due to basic fibroblast growth factor was not affected. In conclusion, endothelin has mitogenic effects on human prostatic smooth muscle cells through activation of both endothelin ET(A) and ET(B) receptors via different signalling pathways from basic fibroblast growth factor. This may contribute to smooth muscle hyperplasia associated with benign prostatic hyperplasia.
Insights
Endothelins stimulate human prostatic smooth muscle cell growth by activating both endothelin ET(A) and ET(B) receptors. This finding offers insights into smooth muscle hyperplasia in benign prostatic hyperplasia.
Area of Science:
- Urology
- Cell Biology
- Endocrinology
Background:
- Benign prostatic hyperplasia (BPH) involves smooth muscle hyperplasia.
- Endothelins are potent vasoconstrictors with known mitogenic properties.
Purpose of the Study:
- To investigate the effects of endothelins on human prostatic smooth muscle cell proliferation.
- To determine the specific endothelin receptor subtypes involved in mediating these effects.
Main Methods:
- Human prostatic smooth muscle cells were treated with endothelin-1 and endothelin-3.
- Cell proliferation and DNA synthesis were measured.
- Subtype-selective antagonists (BQ-123 for ET(A) and BQ-788 for ET(B)) were used.
- Pertussis toxin was employed to investigate signaling pathways.
Main Results:
- Endothelin-1 and endothelin-3 induced a dose-dependent increase in DNA synthesis and cell growth.
- Both endothelin ET(A) and ET(B) receptors mediated the mitogenic effects.
- Pertussis toxin inhibited endothelin-induced mitogenesis but not that induced by basic fibroblast growth factor.
Conclusions:
- Endothelin exerts mitogenic effects on human prostatic smooth muscle cells via both ET(A) and ET(B) receptors.
- The signaling pathways differ from those of basic fibroblast growth factor.
- These findings suggest a role for endothelins in the smooth muscle hyperplasia associated with BPH.