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The regulation of mitogenesis and apoptosis in response to the persistent stimulation of α 1 ‐adrenoceptors: a possible role of 15‐lipoxygenase
Author(s) -
Nishio Eisuke,
Watanabe Yasuhiro
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701529
Subject(s) - nordihydroguaiaretic acid , phenylephrine , lipoxygenase , endocrinology , apoptosis , stimulation , dna fragmentation , medicine , fragmentation (computing) , biology , chemistry , programmed cell death , biochemistry , enzyme , ecology , blood pressure
1 Activation of α 1 ‐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 α 1 ‐adrenoceptor‐stimulated VSMCs growth through mutually exclusive biological functions, that is cell proliferation and cell death. 2 Phenylephrine (10 μ M ), a specific α 1 ‐adrenoceptor agonist, enhanced [ 3 H]‐thymidine incorporation by 300% above basal. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, caused 36 and 50% decrease in phenylephrine (10 μ M )‐stimulated [ 3 H]‐thymidine incorporation at concentrations of 1 μ M and 10 μ M respectively. 3 Inversely, treatment of phenylephrine (10 μ M )‐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 μ M )‐level at concentrations of 0.1 μ M , 1 μ M and 10 μ M , 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 μ M and 10 μ M of 15HETE, respectively, as compared with phenylephrine (10 μ M ) in the presence of NDGA (10 μ M ). 4 Furthermore, we performed the time‐course analysis of Bcl‐2 protein expression in phenylephrine (10 μ M )‐stimulated VSMCs. The expression of Bcl‐2 protein disappeared after a 2 h incubation in the presence of NDGA (10 μ M ), but remained stable after a 2 h incubation period in the absence of NDGA (10 μ M ). 5 These results suggest that the lipoxygenase pathway is involved in cell proliferation by preventing apoptosis through the level of Bcl‐2 protein expression.