Abstract 969: Blockade of Angiotensin II Receptor Enhances the Inhibitory Effect of Statin on Vascular Calcification in Renal Failure Rats
Background: Vascular calcification, which leads to cardiovascular event, is a critical problem in patients with chronic kidney disease (CKD). In this study, we examined whether statin and angiotensin II type I receptor blocker (ARB) can prevent aortic calcification in rats with chronic renal failure (CRF).
Methods and Results: CRF rats, which were induced by feeding 0.75% adenine (AD)-containing diet, were orally offered pravastatin (PR: 1–100 mg/kg/day) and/or olmesartan (OL: 1–10 mg/kg/day) throughout experiments (8 weeks). The adenine diet induced severe renal dysfunction (10-fold increase of serum creatinine and massive microalbuminuria) with huge elevation in blood pressure (BP). The CRF rats had extensive calcification in aortic media in morphometric assessment by von-Kossa staining. Either pravastatin or olmesartan alone dose-dependently inhibited the aortic calcification, and calcium content in dried aorta was significantly attenuated by each administration (μg/mg dry weight: Cont: 0.09±0.03, AD: 18.66±7.32, PR: 1.02±1.87, OL: 4.23±1.86, at maximum dose). The significant inhibition by pravastatin, which was found even at lowest dose, was independent of renoprotective, BP-lowering, and lipid-lowering effects, suggesting that the preventive potential for aortic calcification via its pleiotropic effect. Intriguingly, combined use of both agents at lowest dose synergistically attenuated not only the aortic calcification but also cell apoptosis as TUNEL-positive, which was co-localized with the medial calcified lesion. In addition, in vitro model using cultured VSMC, each agent mimicked inhibition of inorganic phosphate-induced VSMC calcification, and combined treatment additively retarded the calcium deposition in VSMC as well as synergistic benefit in animal experiment. These inhibitory effects were, at least in part, resulted from inhibiting apoptosis via restoration of cell survival Gas6-Axl pathway.
Conclusion: Statin or ARB might exert the potent protective effect on the vascular calcification in CKD, and combination therapy using ARB with statin synergistically shows the preventive capacities to a greater extent than monotherapy with either drug, suggesting a possibility for potential therapeutic strategy.