Losartan Inhibits Vascular Calcification by Suppressing the BMP2 and Runx2 Expression in Rats In Vivo

Abstract

The blockade of renin-angiotensin II system has been shown to reduce morbidity and mortality in hypertension, atherosclerosis, diabetes and chronic kidney disease. Since vascular calcification (VC) is commonly found in these diseases, the aim of this study was to examine whether or not losartan, a widely used angiotensin II receptor blockers, inhibits VC in rats in vivo. A rat model of VC was generated by treating rats with a combination of warfarin and vitamin K1. Two weeks after the treatments, the rats were treated with vehicle or without losartan (100 ng/kg/day) for 2 weeks. At the end of the experiments, aortic arteries were isolated for the examination of calcification morphology, mRNA and protein expression of BMP2 and Runx2, and osteoblast differentiation. Warfarin and vitamin K instigated vascular remodeling with calcified plaques in the aortic arteries in rats. Losartan significantly attenuated warfarin- and vitamin K-induced vascular injury and calcification. Consistently, losartan suppressed the levels of mRNA and protein expression of BMP2 and Runx2, two key factors for VC. Further, vascular calcified lesion areas expressed angiotensin II 1 receptor (AT1R). Finally, losartan treatment significantly inhibited apoptosis in vascular smooth muscle cell (VSMC) in rat arteries. We conclude that losartan suppresses VC by lowering the expression of AT1R, Runx2 and BMP2, and by inhibiting the apoptosis of VSMC in rat aortic arteries.

Intermedin1–53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of α-Klotho

“…Numerous studies, including our previous work, have shown that paracrine/autocrine factors are involved in vascular calcification and many agents could modify vascular calcification, including sodium pyrophosphate, 50 lanthanum carbonate, 51 angiotensin II receptor blocker losartan, 52 and the bioactive peptide adrenomedullin. 12 IMD has several benefits for inhibiting vascular calcification.…”

Menaquinone‑4 modulates the expression levels of calcification‑associated factors to inhibit calcification of rat aortic vascular smooth muscle cells in a dose‑dependent manner

“…Previous studies have shown that VC is cell-mediated and inactive process, which may result from the osteogenic differentiation of VSMCs and subsequent extracellular matrix mineralization (28)(29)(30). Runx2, which is a central transcription factor, is necessary for osteogenic matrix gene expression, bone formation, VSMC calcification and differentiation (22,31,32). Furthermore, the increasing phosphate concentration in vitro results in upregulation of Runx2 expression and downregulation of smooth muscle-specific gene expression (10).…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…When rabbits fed an atherogenic diet to induce atherosclerosis and arterial calcification are administrated with an ARB, calcification together with expression of BMP2 and osteocalcin are attenuated (33). Rats treated with warfarin and vitamin K with or without AT 1 R blocker losartan also demonstrate that the ARB reduces aortic calcification with suppression of BMP2 and Runx2 (570). ANG II also upregulates the receptor activator of NF-B ligand (RANKL) system in VSMCs, which is known to increase BMP2 expression, and bone-related genes cbfa1 and msx2, which cumulatively promote vascular calcification, and enhanced ACE expression and AT 1 R mRNA in vivo.…”