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

Purpose: We explored the effects of rosuvastatin, aspirin, ticagrelor, and clopidogrel, alone or in combinations on the progression of atherosclerosis and inflammasome activation in diabetic mice. Statins and ticagrelor increase the production of 15-epi-lipoxin A₄ via cyclooxygenase-2. Aspirin alone increases 15-epi-lipoxin A₄, but when combined with statins, cyclooxygenase-2 is completely blocked. Methods: ApoE^−/−/db⁺/db⁺ double-knockout mice received rosuvastatin (5 mg/kg/day), aspirin (25 mg/kg/day), ticagrelor (300 mg/kg/day), clopidogrel (75 mg/kg/day), or their combination for 14 weeks. Serum 15-epi-lipoxin A₄ levels and aortic wall cholesterol content, IL-1β, IL-6, and TNF-α levels, and plaque area were assessed. Results: Aspirin, ticagrelor, and rosuvastatin increased 15-epi-lipoxin A₄ levels. The combination of rosuvastatin + ticagrelor provided an additive effect. Aspirin attenuated the effect of both ticagrelor and rosuvastatin. Aspirin, ticagrelor, and rosuvastatin reduced the area of the atherosclerotic plaque. The combination of ticagrelor + rosuvastatin provided additive effects. 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 an additive effect. Aspirin, ticagrelor, and rosuvastatin all decreased TNF-α levels. Aspirin attenuated the effect of both ticagrelor and rosuvastatin, and there was no additive effect of combining ticagrelor + rosuvastatin. Conclusions: 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.