Abstract 1454: Chronic Treatment of ApoE-Deficient Mice with Rosuvastatin Changes Plaque Extracellular Matrix Composition: Implications for Plaque Stability
Objectives: HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events. The aim of the present study was to investigate the effect of rosuvastatin on extracellular matrix (ECM) composition, since the ECM plays a crucial role in the stability of atherosclerotic plaques. For this purpose chronic rosuvastatin treatment was initiated in middle-aged ApoE-deficient mice with pre-existing atherosclerosis.
Methods: ApoE-deficient mice were kept on normal chow diet. At the age of 20 weeks the animals received normal chow or chow containing rosuvastatin (20 mg/kg rosuvastatin per day, p.o.). After 32 weeks of treatment the plaque morphology and ECM composition, smooth muscle cell (SMC) accumulation and plaque calcification were analysed at the aortic root using histochemistry and immunohistochemistry.
Results: Rosuvastatin had no effect on total cholesterol plasma levels and plaque size. However, cell density was reduced in the plaques of rosuvastatin-treated mice (2.1 ± 0.2 cells/1000 μm2 versus 1.5 ± 0.1 cells/1000 μm2, mean ± SEM, n =10; p < 0.05). Detailed analysis of proteoglycan composition revealed a dramatic accumulation of the collagen binding proteoglycans decorin and biglycan. In contrast, perlecan was not changed by rosuvastatin treatment and versican was hardly detectable. Plaque calcification and SMC cell content were not changed. Importantly however, collagen was strongly increased and the staining of neoepitopes that are generated by matrix metalloproteinase-mediated cleavage of collagen was decreased by rosuvastatin treatment. Moreover, cyclooxygenase-2 and hyaluronan synthase-2 expression were markedly inhibited in rosuvastatin-treated ApoE deficient mice.
Conclusions: This is the first report showing that treatment with statins affects proteoglycan composition of atherosclerotic lesions of ApoE-deficient mice. Specifically, accumulation of collagen binding proteoglycans, decorin and biglycan, was increased and collagen degradation was decreased by treatment with rosuvastatin. These changes might be responsible for the increased collagen accumulation in fibrous caps and support the hypothesis that rosuvastatin promotes the development of a stable plaque phenotype.