PMID- 11486244
OWN - NLM
STAT- MEDLINE
DCOM- 20011210
LR  - 20190724
IS  - 0160-2446 (Print)
IS  - 0160-2446 (Linking)
VI  - 38
IP  - 3
DP  - 2001 Sep
TI  - Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine 
      expression, and macrophage accumulation in apolipoprotein E-deficient mice.
PG  - 395-405
AB  - Recent data suggest that angiotensin II AT1 receptor antagonists may be 
      beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor 
      antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic 
      lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) 
      E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion 
      development after a 12-week treatment period (lesion size: irbesartan treated, 
      20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 
      0.001). This effect was not due to an effect of irbesartan on lipoprotein levels 
      because irbesartan slightly increased total cholesterol levels and decreased the 
      ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the 
      atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of 
      macrophages in the lesions of control mice, whereas sections from 
      irbesartan-treated animals only showed occasional labeling in the lesion area. 
      These data suggest that irbesartan inhibits monocyte/macrophage influx into the 
      vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 
      (MCP-1), as well as other chemokines involved in macrophage infiltration into the 
      lesion area, were measured in the aortic sinus of control and irbesartan-treated 
      animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as 
      MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 
      occurred without an effect on CCR2, the receptor of MCP-1. Expression of 
      macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in 
      atherosclerotic lesions, was also reduced after irbesartan treatment, without 
      effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the 
      expression of the angiogenic chemokines KC and MIP-2, which are functionally 
      related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 
      was upregulated. These data suggest that inhibition of the inflammatory component 
      of lesion progression plays an important role in the inhibitory effect of AT1 
      receptor antagonists on atherosclerotic lesion formation.
FAU - Dol, F
AU  - Dol F
AD  - Sanofi-Synthelabo Recherche, Toulouse, France.
FAU - Martin, G
AU  - Martin G
FAU - Staels, B
AU  - Staels B
FAU - Mares, A M
AU  - Mares AM
FAU - Cazaubon, C
AU  - Cazaubon C
FAU - Nisato, D
AU  - Nisato D
FAU - Bidouard, J P
AU  - Bidouard JP
FAU - Janiak, P
AU  - Janiak P
FAU - Schaeffer, P
AU  - Schaeffer P
FAU - Herbert, J M
AU  - Herbert JM
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Cardiovasc Pharmacol
JT  - Journal of cardiovascular pharmacology
JID - 7902492
RN  - 0 (Angiotensin Receptor Antagonists)
RN  - 0 (Antihypertensive Agents)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CCL3)
RN  - 0 (Chemokine CCL4)
RN  - 0 (Chemokines, CXC)
RN  - 0 (Lipids)
RN  - 0 (Macrophage Inflammatory Proteins)
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Tetrazoles)
RN  - J0E2756Z7N (Irbesartan)
SB  - IM
MH  - *Angiotensin Receptor Antagonists
MH  - Animals
MH  - Antihypertensive Agents/pharmacology
MH  - Aorta/pathology
MH  - Apolipoproteins E/genetics/*metabolism
MH  - Arteriosclerosis/*drug therapy/metabolism/pathology
MH  - Biphenyl Compounds/administration & dosage/*pharmacology
MH  - Chemokine CCL2/genetics/metabolism
MH  - Chemokine CCL3
MH  - Chemokine CCL4
MH  - Chemokines, CXC/genetics/metabolism
MH  - Female
MH  - Humans
MH  - Irbesartan
MH  - Lipids/blood
MH  - Macrophage Inflammatory Proteins/genetics/metabolism
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Receptor, Angiotensin, Type 1
MH  - Receptors, Chemokine/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tetrazoles/administration & dosage/*pharmacology
EDAT- 2001/08/07 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/08/07 10:00
PHST- 2001/08/07 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/08/07 10:00 [entrez]
AID - 10.1097/00005344-200109000-00008 [doi]
PST - ppublish
SO  - J Cardiovasc Pharmacol. 2001 Sep;38(3):395-405. doi: 
      10.1097/00005344-200109000-00008.