PMID- 11336104
OWN - NLM
STAT- MEDLINE
DCOM- 20011018
LR  - 20190724
IS  - 0160-2446 (Print)
IS  - 0160-2446 (Linking)
VI  - 37
IP  - 5
DP  - 2001 May
TI  - Doxazosin inhibits monocyte chemotactic protein 1-directed migration of human 
      monocytes.
PG  - 532-9
AB  - Monocyte chemotactic protein 1 (MCP-1)-directed transendothelial migration of 
      monocytes plays a key role in the early development of atherosclerosis. Migration 
      of monocytes requires degradation of extracellular matrices, a process that 
      involves matrix metalloproteinases (MMP) and tissue inhibitors of MMPs (TIMP). 
      Recent studies suggest that the alpha1-adrenergic receptor antagonist doxazosin 
      (Dox) might have antiatherosclerotic effects, although the underlying mechanisms 
      are poorly understood. The purpose of the present study was to determine the 
      effects of Dox on MCP-1-directed monocyte migration, 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 microM of 69.5+/-5.9% in 
      HPBM and 72.2+/-3.2% in THP-1 cells. Dox blocked migration even after 
      pretreatment with phenoxybenzamine, an irreversible alpha1-adrenergic receptor 
      antagonist (HPBM: phenoxybenzamine 1 microM + Dox 10 microM, 71.9+/-2.2% 
      inhibition; THP-1 cells: phenoxybenzamine 1 microM + Dox 10 microM: 78+/-7.7% 
      inhibition), suggesting that the antimigratory activity of Dox is mediated 
      through a novel mechanism unrelated to its blocking of the alpha1-adrenergic 
      receptor. Dox (10 microM) inhibited 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 microM. The 
      present study demonstrates 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.
FAU - Kintscher, U
AU  - Kintscher U
AD  - University of California, Los Angeles, School of Medicine, Division of 
      Endocrinology, Diabetes and Hypertension, 90095, USA.
FAU - Kon, D
AU  - Kon D
FAU - Wakino, S
AU  - Wakino S
FAU - Goetze, S
AU  - Goetze S
FAU - Graf, K
AU  - Graf K
FAU - Fleck, E
AU  - Fleck E
FAU - Hsueh, W A
AU  - Hsueh WA
FAU - Law, R E
AU  - Law RE
LA  - eng
GR  - HL 58328/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Cardiovasc Pharmacol
JT  - Journal of cardiovascular pharmacology
JID - 7902492
RN  - 0 (Adrenergic alpha-Antagonists)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - NW1291F1W8 (Doxazosin)
SB  - IM
MH  - Adrenergic alpha-Antagonists/*pharmacology
MH  - Cell Movement/*drug effects/physiology
MH  - Chemokine CCL2/*antagonists & inhibitors/pharmacology
MH  - Doxazosin/*pharmacology
MH  - Humans
MH  - Matrix Metalloproteinase 9/drug effects/metabolism
MH  - Monocytes/*drug effects/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-1/drug effects/metabolism
MH  - Tumor Cells, Cultured
EDAT- 2001/05/05 10:00
MHDA- 2001/10/19 10:01
CRDT- 2001/05/05 10:00
PHST- 2001/05/05 10:00 [pubmed]
PHST- 2001/10/19 10:01 [medline]
PHST- 2001/05/05 10:00 [entrez]
AID - 10.1097/00005344-200105000-00005 [doi]
PST - ppublish
SO  - J Cardiovasc Pharmacol. 2001 May;37(5):532-9. doi: 
      10.1097/00005344-200105000-00005.