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Abstract: TH-PO551

The Inhibitory Effect of Zinc Chloride on Phosphate-Induced Calcification via Suppression of HIF1a Expression in Human Vascular Smooth Muscle Cells

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Tokumoto, Masanori, Department of Internal Medicine, Fukuoka Dental College, Sawara-ku, FUKUOKA, Japan
  • Yamada, Shunsuke, Kyushu University, Fukuoka, Japan
  • Nakano, Toshiaki, Kyushu University, Fukuoka, Japan
  • Kitazono, Takanari, Department of Medicine and Clinical Science, Fukuoka, Japan
  • Ooboshi, Hiroaki, Fukuoka Dental College, Fukuoka, Japan
Background

<span lang="EN-US" style="font-family:century,serif; font-size:10.5pt; margin:0px"><font color="#000000">Vascular calcification is a life-threatening pathophysiological abnormality in CKD. It was demonstrated that phosphate (P), a main inducer of vascular calcification, enhances oxidative stress and its resultant inflammation, leading to osteochondrogenic differentiation and calcification in cultured vascular smooth muscle cells (VSMCs). Because plasma Zn levels are low in CKD patients and Zn has anti-inflammatory effects, we examined effects of ZnCl2 on P-induced inflammation, osteochondrogenic differentiation, and calcification in human VSMCs.</font></span>

Methods

Human VSMCs were cultured in DMEM plus 10%FCS and 2.0mM P with 0, 0.5, 1, 5, 10, 50, or 100 mM ZnCl2 for 3, 7 or 14 days. The precipitated calcium contents and expression of inflammatory mediators, osteochondrogenic differentiation markers and its inducers, including HIF1a and VEGF, were evaluated.

Results

At 14 days, ZnCl2 inhibited calcification in a concentration-dependent manner, and high concentrations (>=10mM) of ZnCl2 reduced calcification by almost 90% (p<0.01). Moderate to high concentrations (>=5mM) of ZnCl2 suppressed expression of osteochondrogenic differentiation markers (SOX9, MSX2, and RUNX2) and inducers (BMP2, PiT1, and MMP2) (p<0.01). Moreover, moderate to high concentrations of ZnCl2 suppressed IL-1b expression at earlier time points (3 and 7 days, p<0.01) and also inhibited expression of HIF1a and VEGF, a downstream gene of HIF1, through the period (p<0.01). Expression of both HIF1a and VEGF positively correlated with IL-1b expression, precipitated Ca content, and expression of BMP2, SOX9, MSX2, RUNX2, PiT1, and MMP2, respectively (p<0.01).

Conclusion


<font color="#000000"><span lang="EN-US" style="font-family:century,serif; font-size:10.5pt; margin:0px">ZnCl2 can directly inhibit P-induced inflammation and HIF1</span><span lang="EN-US" style="font-family:symbol; font-size:10.5pt; margin:0px"><span style="margin:0px">a</span></span><span lang="EN-US" style="font-family:century,serif; font-size:10.5pt; margin:0px"> expression, leading to suppression of osteochondrogenic differentiation and calcification in human VSMCs.</span></font>

Funding

  • Government Support - Non-U.S.