Rosuvastatin displays anti-atherothrombotic and anti-inflammatory properties in apoE-deficient mice.
Inflammation contributes importantly to all stages of atherosclerosis, including the onset of acute thrombotic complications. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. Moreover, statins have been shown to possess several pleiotropic properties independent of cholesterol lowering in experimental settings. Based on these premises, we investigated the anti-inflammatory and anti-atherothrombotic properties of rosuvastatin in vivo, testing its effect on cholesterol and monocyte accumulation, and on adhesion molecules and tissue factor (TF) expression. ApoE-deficient female mice were fed a cholesterol-rich diet containing rosuvastatin (0, 1, 2 or 10 mg kg(-1)d(-1)) for 12 weeks. Treatment with rosuvastatin did not significantly affect either body weight gain or plasma total cholesterol (C) and triglyceride levels. However, rosuvastatin treatment dose-dependently reduced ICAM-1 expression in the aortic valves (V) (up to 40% inhibition, p<0.05) and in the proximal segment of the ascending aorta (AA) (-50%, p<0.001). Similarly, rosuvastatin inhibited VCAM-1 expression in the V (-40%) and in the AA (-35%, p<0.05). Moreover, there was a reduced accumulation of macrophages in the V in a dose-dependent and statistically significant manner (-45%, p<0.01). These anti-inflammatory effects were reflected in a reduction of cholesterol deposition in the entire aorta, both in the free and in the esterified form. Finally, the expression of tissue factor, the most potent pro-thrombogenic agent, was consistently reduced in AA by rosuvastatin treatment (-71%, p<0.001). Altogether, these data demonstrate that rosuvastatin has anti-inflammatory and anti-atherothrombotic activities in apoE-deficient mice that could translate in a beneficial effect on atherogenesis.
Monetti
M
M
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Canavesi
M
M
Camera
M
M
Parente
R
R
Paoletti
R
R
Tremoli
E
E
Corsini
A
A
Bellosta
S
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001021:Aortic Valve / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D002317:Cardiovascular Agents; D002791:Cholesterol, Dietary; D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000068718:Rosuvastatin Calcium; D013925:Thromboplastin; D002784:Cholesterol