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Cardiovascular Research Advance Access originally published online on October 25, 2007
Cardiovascular Research 2008 77(1):221-230; doi:10.1093/cvr/cvm049
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Nitric oxide regulates vascular calcification by interfering with TGF-β signalling

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 Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, D.W.C.L.A., Kyo-tanabe, Kyoto 610-0395, Japan
3 The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

* Corresponding author. Tel: +81 0774 65 8629; fax: +81 0774 65 8479. E-mail address: ykanno{at}dwc.doshisha.ac.jp (Y.K.). Tel: +81 562 46 2311 (ext. 5401); fax: +81 562 46 8479. E-mail address: kmatsu30{at}nils.go.jp (K.M.)

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

Conclusion: Our data show that NO prevents differentiation of VSMCs into osteoblastic cells by inhibiting TGF-β signalling 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 ageing; Diabetes mellitus

Time for primary review: 19 days


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