Unravelling the Interaction of Aspirin, Ticagrelor and Rosuvastatin on the Progression of Atherosclerosis and Inflammation in Diabetic Mice

Background: Current guidelines recommend aspirin and statin therapy for patients with stable coronary disease. Following acute coronary syndromes and revascularization procedures, P2Y₁₂ inhibitors are added. Statins and ticagrelor increase extracellular adenosine levels with downstream S-nitrosylation of cyclooxygenase-2 and increased production of 15-epi-lipoxin A₄. Aspirin alone increases the production of 15-epi-lipoxin A₄, but when combined with statins, cyclooxygenase-2 is completely blocked. We explored the effects of rosuvastatin, aspirin, ticagrelor and clopidogrel, alone or in combinations on the progression of atherosclerosis and arterial wall inflammasome activation in diabetic mice.
Methods: ApoE^-/-/db⁺/db⁺ double-knockout mice at age of 6 weeks received rosuvastatin (5mg/kg/d), aspirin (25mg/kg/d), ticagrelor (300mg/kg/d), clopidogrel (75mg/kg/d) or their combination. At age of 20 weeks, serum 15-epi-lipoxin A₄ levels were determined. Animals were sacrificed and the aortas collected and assessed for cholesterol content, IL-1β, IL-6 and TNFα levels, and stained with Sudan IV for assessment of atherosclerosis.
Results: Aspirin, ticagrelor and rosuvastatin all increased 15-epi-lipoxin A₄ levels. The combination of rosuvastatin and ticagrelor provided an additive effect. Aspirin attenuated the effect of both ticagrelor and rosuvastatin to levels below that of aspirin. Aspirin, ticagrelor and rosuvastatin all equally reduced the area of the atherosclerotic plaque. The combination of ticagrelor and rosuvastatin provided an additive effect. In contrast, there was a negative interaction when aspirin was combined with ticagrelor or rosuvastatin. Aspirin, ticagrelor and rosuvastatin decreased serum IL-1β and IL-6 levels. There was no interaction between aspirin and ticagrelor or aspirin and rosuvastatin, whereas combining rosuvastatin and ticagrelor provided additive effect. Aspirin, ticagrelor and rosuvastatin all decreased TNFα levels. Aspirin attenuated the effect of both ticagrelor and rosuvastatin and there was no additive effect of combining ticagrelor and rosuvastatin. Clopidogrel had no significant effects and did not alter the effects of the other drugs.
Conclusions: Aspirin, rosuvastatin and ticagrelor, but not clopidogrel, attenuated inflammation and atherosclerosis. We found an intricate interaction between aspirin, ticagrelor and rosuvastatin, as aspirin reduced both ticagrelor and rosuvastatin ability to ameliorate inflammation and atherosclerosis. In contrast, we found additive effects when ticagrelor and rosuvastatin were combined.