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Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 25, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm049
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Nitric oxide regulates vascular calcification by interfering with TGF-ß signaling

Yosuke Kanno1,2,, Takeshi Into1, Charles J. Lowenstein3 and Kenji Matsushita1,

1 Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka-cho, Obu, Aichi 474-8511, Japan
2 Dept. of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, D.W.C.L.A., Kyo-tanabe 610-0395 Kyoto, Japan
3 The Johns Hopkins University School of Medicine, Baltimore, MD, 21205

* Corresponding Author: Yosuke Kanno, Dept. of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, D.W.C.L.A., Kyo-tanabe 610-0395 Kyoto, Japan Telephone +81-0774-65-8629; Fax +81-0774-65-8479; E-mail: ykanno{at}dwc.doshisha.ac.jp Kenji Matsushita, 36-3 Gengo, Morioka-cho, Obu, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan; Telephone +81-562-46-2311 (ext. 5401); Fax +81-562-46-8479; E-mail: kmatsu30{at}nils.go.jp

Aim: Vascular calcification often occurs with advancing age, atherosclerosis, and metabolic disorders such as diabetes mellitus and end-stage renal disease. Vascular calcification is associated with cardiovascular events and increased mortality. Nitric oxide (NO) is crucial for maintaining vascular function, but little is known about how NO affects vascular calcification. The aim of this study was to examine the effect of NO on vascular calcification.

Methods: In this study, we examined the inhibitory effects of NO on calcification of murine vascular smooth muscle cells (VSMCs) in vitro. We measured calcium concentration, alizarin red staining, and alkaline phosphatase activity to examine the effect of NO on calcification of VSMCs and differentiation of VSMCs into osteoblastic cells. We also determined gene expression and levels of phosphorylation of Smad2/3 by RT-PCR and Western blotting.

Results: NO inhibited calcification of VSMCs and differentiation of VSMCs into osteoblastic cells. An inhibitor of cGMP-dependent protein kinase (PKG) restored the inhibition by NO of osteoblastic differentiation and calcification of VSMCs. NO inhibited transforming growth factor-ß (TGF-ß?-induced phosphorylation of Smad2/3 and expression of TGF-ß-induced genes such as plasminogen activator inhibitor-1 (PAI-1). In addition, NO inhibited expression of the TGF-ß receptor ALK5.

Conclusion: Our data show that NO prevents differentiation of vascular smooth muscle cells into osteoblastic cells by inhibiting TGF-ß signaling through a cGMP-dependent pathway. Our findings suggest that NO may play a beneficial role in atherogenesis in part by limiting vascular calcification.

KEYWORDS atherosclerosis; vascular calcification; vascular aging; diabetes mellitus

Time for primary review: 19 days


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