Hydroxyurea Regressed Atherosclerosis Plaques in ApoE-/- Mice: A Discovery Based on Clinic

Abstract

Background: A 58-year-old lady was introduced to the clinic because of acute coronary syndrome combined with essential thrombocythemia. After coronary artery bypass grafting. After treating her with aspirin, statins and hydroxyurea (HU), the plaques in her coronary arteries showed improvement dramatically. Here, we aim to investigate that HU might regress atherosclerosis plaques in ApoE−/− mice and the potential mechanism.Methods: Wild-type (C57BL/6, n = 8) and Apolipoprotein E knockout (ApoE-/-, n = 40) mice were used in atherosclerosis model and medication groups. The mice were separated into 7 groups, including the normal control group, the atherosclerosis model group, the dual antiplatelet therapy group (aspirin, and clopidogrel bisulfate), the low-dose and high-dose HU therapy groups [aspirin, clopidogrel bisulfate, and HU (10 or 20 mg/kg/day)], the positive medicine group (aspirin, clopidogrel bisulfate, and atorvastatin calcium), and the combined medicine treatment group [aspirin, clopidogrel bisulfate, atorvastatin calcium, and HU (10 mg/kg/day)]. Fasting serum and aortic vessels were obtained after experiment. The aortic oil red O, Hematoxylin-eosin, and full-length oil red O staining was performed to evaluate the HU’s efficacy of anti- atherosclerosis, and the investigation of HU mechanisms was carried out in HepG2 cells for proprotein convertase subtilisin/kexin type 9 (PCSK9) level.Results: The oil red O and H&E staining results came out that HU therapy with antiplatelet showed an obvious effect in decreasing atherosclerosis plaques and the effect of HU therapy (10 or 20 mg/kg) was stronger than dual antiplatelet therapy plus statin, without liver and kidney toxicity observed. Furthermore, the combined drugs with HU (10 mg/kg/day), statin and antiplatelet nearly eliminated the plaques. One of the possible mechanisms of HU might be related with the inhibition of PCSK9.Conclusions: A discovery based on clinic reveals that HU regressed atherosclerosis plaques in ApoE-/- mice, which provides us a new insight into anti-atherosclerosis drugs strategy. PCSK9 could be one of the possible mechanisms and further mechanisms need to be explored.