The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α1‐adrenoceptors: a possible role of 15‐lipoxygenase

• Published in: British journal of pharmacology Vol. 122; no. 7; pp. 1516 - 1522
• Main Authors: Nishio, Eisuke, Watanabe, Yasuhiro
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.1997
• Subjects: apoptosis; lipoxygenase; mitogenesis; Vascular smooth muscle cells; α1‐adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701529

1 Activation of α1‐adrenoceptor stimulation regulates eicosanoid metabolism and growth in vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the functional implications of lipoxygenase pathway in α1‐adrenoceptor‐stimulated VSMCs growth through mutually exclusive biological functions, that is cell proliferation and cell death. 2 Phenylephrine (10 μM), a specific α1‐adrenoceptor agonist, enhanced [3H]‐thymidine incorporation by 300% above basal. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, caused 36 and 50% decrease in phenylephrine (10 μM)‐stimulated [3H]‐thymidine incorporation at concentrations of 1 μM and 10 μM respectively. 3 Inversely, treatment of phenylephrine (10 μM)‐stimulated VSMCs with NDGA induced DNA fragmentation in a dose‐dependent fashion. The level of induction of DNA fragmentation by NDGA was 225, 319 and 406% above the phenylephrine (10 μM)‐level at concentrations of 0.1 μM, 1 μM and 10 μM, respectively. This induction of DNA fragmentation was partially prevented by exogenous 15‐hydroxyeicosatetraenoic acid (15‐HETE). The inhibition of apoptosis was 53 and 63% at concentrations of 5 μM and 10 μM of 15HETE, respectively, as compared with phenylephrine (10 μM) in the presence of NDGA (10 μM). 4 Furthermore, we performed the time‐course analysis of Bcl‐2 protein expression in phenylephrine (10 μM)‐stimulated VSMCs. The expression of Bcl‐2 protein disappeared after a 2 h incubation in the presence of NDGA (10 μM), but remained stable after a 2 h incubation period in the absence of NDGA (10 μM). 5 These results suggest that the lipoxygenase pathway is involved in cell proliferation by preventing apoptosis through the level of Bcl‐2 protein expression.