Modulation of matrix metalloproteinase-1, its tissue inhibitor, and nuclear factor-kappa B by losartan in hypercholesterolemic rabbits

Upregulation of angiotensin II receptor, may be involved in the initiation and progression of atherosclerosis. To examine the contribution of AT1 receptor in the expression of matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor (TIMP-2) in lipid-deposited arterial tissues, New Zealand white rabbits were given high-cholesterol chow (with losartan 25 mg/d or vehicle) for 10 weeks. Losartan reduced the areas of sudanophilia in the aorta of rabbits fed high-cholesterol diet (p < 0.01 vs. control). Losartan also significantly decreased the enhanced mRNA expression of MMP-1 and TIMP-2 in aortas of rabbits with high-cholesterol diet. Losartan-treated rabbits revealed a reduction in immunohistochemical expression of MMP-1, whereas TIMP-2 expression became localized to the intima. In addition, losartan treatment reduced the activation of NF-kappa B by inhibiting the degradation of its inhibitor I kappa-B alpha. These observations demonstrate that AT1 receptor blockade with losartan reduces lipid deposition and exerts potent inhibitory effects on NF-kappa B activation and modulates the expression of MMP-1 and TIMP-2 in hypercholesterolemic rabbits.