Abstract Statins efficiently prevent cardiovascular events by lipid-dependent and independent mechanisms. We hypothesize that part of these protective effects could be associated with an increased extracellular adenosine signaling. We demonstrated previously that aortic valves obtained from patients with calcific aortic valve disease (CAVD) disclosed disturbances in extracellular adenosine metabolism. This study aimed to analyze the impact of statin treatment on extracellular nucleotides and adenosine metabolism in aortic valves originated from CAVD patients and to elucidate potential mechanisms that are involved in the regulation of ecto-enzyme activities by statins. Aortic valves of CAVD patients treated with statins (n = 45) revealed higher adenosine production and its lower degradation than in non-treated patients (n = 28). Statin treatment was also related to the improvement in pre-operative echocardiographic data indicating milder aortic valve stenosis and a better function of the left ventricle. The rates of aortic valve adenosine conversions correlated with plasma lipid profile parameters, within both statin-treated and non-treated groups. Valvular extracellular AMP hydrolysis correlated negatively, while adenosine deamination positively with plasma total and LDL cholesterol. Atorvastatin treatment of murine heart endothelial cells led to the enhanced ecto-5′nucleotidase (CD73) and decreased ecto-adenosine deaminase (eADA) activity. When endothelial cells were stimulated with thrombin that induces endothelial cell exocytosis, activities of both cell-surface CD73 and eADA were increased, while co-treatment with atorvastatin reversed only thrombin-induced eADA activity. In conclusion, early intervention with statins may provide beneficial effects for CAVD therapy. Here, we presented results showing that these protective outcomes could be mediated via the regulation of extracellular adenosine metabolism pathways.

中文翻译：

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他汀类药物治疗钙化性主动脉瓣疾病患者调节主动脉瓣细胞表面细胞外腺苷代谢

摘要 他汀类药物通过脂质依赖性和独立机制有效预防心血管事件。我们假设这些保护作用的一部分可能与增加的细胞外腺苷信号有关。我们之前证明了从钙化性主动脉瓣疾病 (CAVD) 患者获得的主动脉瓣揭示了细胞外腺苷代谢紊乱。本研究旨在分析他汀类药物治疗对 CAVD 患者主动脉瓣细胞外核苷酸和腺苷代谢的影响，并阐明他汀类药物调节外酶活性的潜在机制。与未接受治疗的患者（n = 28）相比，接受他汀类药物治疗的 CAVD 患者（n = 45）的主动脉瓣显示出更高的腺苷产量和更低的降解。他汀类药物治疗还与术前超声心动图数据的改善有关，表明主动脉瓣狭窄程度更轻，左心室功能更好。在他汀治疗组和未治疗组中，主动脉瓣腺苷转化率与血浆脂质参数相关。瓣膜细胞外 AMP 水解呈负相关，而腺苷脱氨与血浆总胆固醇和低密度脂蛋白胆固醇呈正相关。阿托伐他汀对鼠心脏内皮细胞的处理导致 ecto-5' 核苷酸酶 (CD73) 增强和 ecto-腺苷脱氨酶 (eADA) 活性降低。当用诱导内皮细胞胞吐作用的凝血酶刺激内皮细胞时，细胞表面 CD73 和 eADA 的活性均增加，而与阿托伐他汀共同治疗仅逆转凝血酶诱导的 eADA 活性。总之，他汀类药物的早期干预可能为 CAVD 治疗提供有益效果。在这里，我们提出的结果表明这些保护性结果可以通过调节细胞外腺苷代谢途径来介导。