Doxazosin inhibits monocyte chemotactic protein 1-directed migration of human monocytes

Monocyte chemotactic protein 1 (MCP-1)-directed transcndothelial migration of monocytes plays a key role in the early development of atherosclerosis. Migration of monocytes requires degradation of extracellular matrices, a pr ocess that involves matrix metalloproteinases (MMP) and tissue inhibitors o f MMPs (TIMP). Recent studies suggest that the alpha (1)-adrenergic recepto r antagonist doxazosin (Dox) might have antiatherosclerotic effects, althou gh the underlying mechanisms are poorly understood. The purpose of the pres ent study was to determine the effects of Dox on MCP-1-directed monocyte mi gration, MMP-9 activity, and TIMP-1 expression. MCP-1 (50 ng/ml) stimulated migration of human peripheral blood monocytes (HPBM) 2.7 +/- 0.42-fold and THP-1 human monocytes 5.9 +/- 0.83-fold compared with unstimulated control . Dox inhibited MCP-1-induced migration in a dose dependent manner, with a maximal reduction at 10 muM of 69.5 +/- 5.9% in HPBM and 72.2 +/- 3.2% in T HP-1 cells. Dox blocked migration even after pretreatment with phenoxybenza mine, an irreversible alpha (1)-adrenergic receptor antagonist (HPBM: pheno xybenzamine 1 muM + Dox 10 muM, 71.9 +/- 2.2% inhibition; THP-1 cells: phen oxybenzamine 1 muM + Dox 10 muM: 78 +/- 7.7% inhibition), suggesting that t he antimigratory activity of Dox is mediated through a novel mechanism unre lated to its blocking of the alpha (1)-adrenergic receptor. Dox (10 muM) in hibited MMP-9 activity by 67.6 +/- 10.5%, whereas MMP-9 protein levels were not affected. Also, Dox increased PMA-induced-tissue inhibitor of MMPs-1 ( TIMP-1) expression by 134.4 +/- 6.6%. Dox 10 mum. The present study demonst rates a potential novel antiatherosclerotic action of Dox by blocking MCP-1 -directed monocyte migration, which might be partly mediated by inhibition of MMP-9 activity.