Iijima Katsuya, Ito Yuki, Son Bo-Kyung, Akishita Masahiro, Ouchi Yasuyoshi
Institute of Gerontology, The University of Tokyo.
J Atheroscler Thromb. 2014;21(9):917-29. doi: 10.5551/jat.23218. Epub 2014 May 19.
Vascular calcification is a critical problem in patients with chronic kidney disease (CKD). In this study, we examined the effects of a HMG Co-A reductase inhibitor (statin) and an angiotensin Ⅱ type 1 receptor blocker (ARB) on renal failure-induced vascular calcification.
Severe renal failure was induced in rats by feeding a 0.75% adenine diet for six weeks. These rats had hyperphosphatemia, hypertension and hypercholesterolemia. A histological assessment showed extensive linear calcification in the aortic media and a significant increase in the aortic content of calcium and phosphorus. Oral administration of pravastatin (a statin; 1-10 mg/kg/day) or olmesartan (an ARB; 1-10 mg/kg/day) dose-dependently inhibited the aortic calcification in parallel with their renoprotective, lipid-lowering and blood pressure-lowering effects. Of note, the lowest dose of pravastatin inhibited aortic calcification with no influence on the renal function, BP and cholesterol, suggesting that it has direct vasoprotective properties. Intriguingly, the combined administration of pravastatin and olmesartan at the lowest doses synergistically ameliorated the aortic calcification, and the protective effect was at least partly attributable to the inhibition of RF-induced apoptosis in the aortic wall. An in vitro model of inorganic phosphate (Pi)-induced vascular smooth muscle cell calcification mimicked these effects of pravastatin and olmesartan, and the beneficial effect of the combination was attributable to the inhibitory effects on Pi-induced apoptosis via the restoration of the Gas6/Axl-mediated anti-apoptotic pathway.
A statin and an ARB exerted potent protective effects against vascular calcification due to CKD, probably through their pleiotropic effects. In addition, combination therapy with pravastatin and olmesartan may provide a new therapeutic strategy for the prevention of vascular calcification.
血管钙化是慢性肾脏病（CKD）患者的一个关键问题。在本研究中，我们研究了一种HMG辅酶A还原酶抑制剂（他汀类药物）和一种血管紧张素Ⅱ1型受体阻滞剂（ARB）对肾衰竭诱导的血管钙化的影响。
通过给大鼠喂食0.75%腺嘌呤饮食六周诱导严重肾衰竭。这些大鼠出现高磷血症、高血压和高胆固醇血症。组织学评估显示主动脉中膜有广泛的线性钙化，主动脉钙和磷含量显著增加。口服普伐他汀（一种他汀类药物；1 - 10毫克/千克/天）或奥美沙坦（一种ARB；1 - 10毫克/千克/天）剂量依赖性地抑制主动脉钙化，同时具有肾脏保护、降脂和降压作用。值得注意的是，最低剂量的普伐他汀抑制主动脉钙化，而对肾功能、血压和胆固醇无影响，表明它具有直接的血管保护特性。有趣的是，最低剂量的普伐他汀和奥美沙坦联合给药协同改善主动脉钙化，且保护作用至少部分归因于对肾衰竭诱导的主动脉壁细胞凋亡的抑制。无机磷酸盐（Pi）诱导的血管平滑肌细胞钙化的体外模型模拟了普伐他汀和奥美沙坦的这些作用，联合用药的有益作用归因于通过恢复Gas6/Axl介导的抗凋亡途径对Pi诱导的细胞凋亡的抑制作用。
他汀类药物和ARB对CKD引起的血管钙化发挥了强大的保护作用，可能是通过它们的多效性作用。此外，普伐他汀和奥美沙坦联合治疗可能为预防血管钙化提供一种新的治疗策略。
