| COMMENTARIES |
Effect of Nitric Oxide on the Development of Vascular Calcification
Yosuke Kanno, Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women's Collage of Liberal Arts, Kyo-tanabe 610-0395 Kyoto, Japan
Please address correspondence to:
Yosuke Kanno
Dept. of Clinical Pathological Biochemistry
Faculty of Pharmaceutical Science
Doshisha Women's Collage of Liberal Arts
Kyo-tanabe 610-0395 Kyoto, Japan
Tel: +81-0774-65-8629
Fax: +81-0774-65-8479;
Email: ykanno@dwc.doshisha.ac.jp
The Mechanism on the Development of Vascular Calcification
Vascular calcification occurs in many diseases, including atherosclerosis, diabetes, and uremia [1-3]. Deposition of calcification in arteries diminishes arterial wall elasticity, obstructs blood flow, and can lead to heart attacks and stroke [4]. The presence of calcium deposits in the vessel wall is indicative of advanced atherosclerosis, and the extent of coronary calcification adds independent prognostic significance to conventional risk factors for coronary artery disease. Vascular calcification is a major independent predictor of cardiovascular morbidity and mortality [5].
Vascular smooth muscle cells (VSMCs) play a major role in vascular calcification [6]. VSMCs contribute to the development of an atherosclerotic lesion by migration, proliferation, and secretion of matrix components [7,8]. VSMCs also express many of the calcification-regulating proteins commonly found in bone [9-11]. These proteins have calcium and apatite binding properties, and accumulate in areas of vascular calcification. Among them, transforming growth factor-β (TGF-β) is a key factor in vascular calcification. TGF-β is present in calcified aortic valves [12], and regulates vascular calcification and osteoblastic differentiation of vascular smooth muscle cells [13,14].
In previous study, NO inhibited VSMC calcification and osteoblastic differentiation of VSMCs by interfering with TGF-β signaling [15]. NO produced in the endothelium by eNOS activates smooth muscle cell relaxation and vasodilation by binding to soluble guanylate cyclase, resulting in cGMP production and the activation of signal transduction pathways. Inhibition of guanylate cyclase and PKG reversed the inhibitory effect of NO on vascular calcification and osteoblastic differentiation of VSMCs. Treatment of calcifying VSMCs with cGMP analogue inhibited vascular calcification and osteoblastic differentiation. However, inhibition of guanylate cyclase and PKG did not increase VSMC calcification in the absence of NO donor. On the other hand, inhibition of guanylate cyclase and PKG increased osteoblastic differentiation in the absence of NO donor [15]. These data suggests that another possibility remains that additional cGMP independent pathways such as S-nitrosylation of proteins by NO may also regulate calcification. cGMP/PKG signaling pathway may inhibit osteoblastic differentiation, and NO may inhibit both VSMC calcification and osteoblastic differentiation.
NO reduced TGF-β?signaling by decreasing expression of a TGF-β receptor ALK5, resulting in a down-regulation of TGF-β signal that induces phosphorylation of Smad2/3 [15]. Recently, Saura et al. have shown that NO regulates the transcriptional responses to TGF-β by inhibiting Smad nuclear accumulation via PKG activation in ECs [16]. This important study suggests a molecular mechanism by which NO regulates TGF-β signaling in calcification.
Patients with endothelial dysfunction and defective NO synthesis is at increased risk for cardiovascular events. NO and compounds that induce NO synthesis may be useful not only in inhibiting vascular inflammation, but also in preventing vascular calcification.
References