Pravastatin and olmesartan synergistically ameliorate renal failure-induced vascular calcification.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Gerontology, The University of Tokyo.
Katsuya
K
Iijima
Yuki
Y
Ito
Bo-Kyung
BK
Son
Masahiro
M
Akishita
Yasuyoshi
Y
Ouchi
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002114:Calcinosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000150:complications* / Q000473:pathology; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan; D017035:Pravastatin