Angiotensin AT(1) receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice

Recent data suggest that angiotensin II AT, receptor antagonists may be ben eficial in the treatment of atherosclerosis. To clarify how AT, receptor an tagonists reduce atherosclerosis, the effect of irbesartan on atherosclerot ic lesion development was determined in low-fat, chow-fed apolipoprotein (A po) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesi on development after a 12-week treatment period (lesion size: irbesartan tr eated, 20,524 +/- 4,200 mum(2) vs. control, 99,600 +/- 14,500; 79.4% inhibi tion, p < 0.001). This effect was not due to an effect of irbesartan on lip oprotein levels because irbesartan slightly increased total cholesterol lev els and decreased the ratio of Apo A-I relative to Apo B levels. Immunochem ical analysis of the atherosclerotic lesions using the mac3 monoclonal anti body showed the presence of macrophages in the lesions of control mice, whe reas sections from irbesartan-treated animals only showed occasional labeli ng in the lesion area. These data suggest that irbesartan inhibits monocyte /macrophage influx into the vessel wall. Therefore, expression levels of mo nocyte chemoattractant protein-1 (MCP-1), as well as other chemokines invol ved in macrophage infiltration into the lesion area, were measured in the a ortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in th e lesion area. This effect of irbesartan on MCP-1 occurred without an effec t on CCR2, the receptor of MCPA. Expression of macrophage inflammatory prot ein (MIP)-1 alpha, another CC chemokine expressed in atherosclerotic lesion s, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1 alpha. Concomitantly, the expression of the an giogenic chemokines KC and MIP-2, which are functionally related to interle ukin-8, were downregulated, whereas their shared receptor CXCR2 was upregul ated. These data suggest that inhibition of the inflammatory component of l esion progression plays an important role in the inhibitory effect of AT, r eceptor antagonists on atherosclerotic lesion formation.