Dissertation committee:
Κωνσταντίνος Φίλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Φραγκίσκα Σιγάλα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Τούσουλης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Σχίζας, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευάγγελος Οικονόμου, Επίκουρος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αλέξανδρος Παπαλάμπρος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Νικόλαος Αλεξάκης, Καθηγητής, Τμήμα Ιατρικής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Background: Apolipoprotein E-deficient (Apoe−/−) mice develop atherosclerotic lesions that closely resemble metabolic syndrome in humans. We sought to investigate how rosuvastatin mitigates the atherosclerotic profile of Apoe−/− mice over time and its effects on certain inflammatory chemokines.
Methods: Eighteen Apoe−/− mice were allocated into three groups of six mice each receiving: standard chow diet (SCD; control group); high-fat diet (HFD); and HFD and rosuvastatin at 5 mg/kg/d via intragastric administration for 20 weeks. Analysis of aortic plaques and lipid deposition was conducted by means of en face Sudan IV staining and Oil Red O staining. Serum cholesterol, low-density lipoprotein, high-density lipoprotein, plasma glucose and triglyceride levels were determined at baseline and after 20 weeks of treatment. Serum interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor-α (TNFα) levels were measured by enzyme-linked immunosorbent assay at the time of euthanasia.
Results: The lipidemic profile of Apoe−/− mice on HFD deteriorated over time. Apoe−/− mice on HFD developed atherosclerotic lesions over time. Sudan IV and Oil Red O-stained sections of the aorta revealed increased plaque formation and plaque lipid deposition in HFD-fed mice compared with SCD-fed mice and reduced plaque development in HFD-fed mice treated with rosuvastatin compared with mice not receiving statin treatment. Serum analysis revealed reduced metabolic parameters in HFD-fed mice on rosuvastatin compared with non-statin, HFD-fed mice. At the time of euthanasia, HFD-fed mice treated with rosuvastatin had significantly lower IL6 as well as CCL2 levels when compared with HFD-fed mice not receiving rosuvastatin. TNFα levels were comparable among all groups of mice, irrespective of treatment. IL6 and CCL2 positively correlated with the extent of atherosclerotic lesions and lipid deposition in atherosclerotic plaques.
Conclusion: Rosuvastatin reduced progression of atherosclerotic lesions in HFD-fed Apoe−/− mice and reduced serum IL6 and CCL2 levels after 20 weeks of treatment. Serum IL6 and CCL2 levels correlated with the extent of atherosclerotic lesion. Serum IL6 and CCL2 levels might potentially be used as clinical markers of progression of atherosclerosis during statin treatment for hypercholesterolemia.
Keywords:
Αtherosclerosis, Mice, Apolipoprotein E, Rosuvastatin, Statin, Surgical research
