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Abstract: PO0315

Treatment with β,γ-Methyleneadenosine 5′-Triphosphate Prevents Arterial Media Calcification in a Warfarin Rat Model

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Opdebeeck, Britt, Universiteit Antwerpen Laboratorium voor Pathofysiologie, Wilrijk, Belgium
  • Orriss, Isabel, The Royal Veterinary College Department of Comparative Biomedical Sciences, London, London, United Kingdom
  • Patel, Jessal J., The Royal Veterinary College Department of Comparative Biomedical Sciences, London, London, United Kingdom
  • Van den bergh, Geoffrey, Universiteit Antwerpen Laboratorium voor Pathofysiologie, Wilrijk, Belgium
  • D'Haese, Patrick, Universiteit Antwerpen Laboratorium voor Pathofysiologie, Wilrijk, Belgium
  • Verhulst, Anja, Universiteit Antwerpen Laboratorium voor Pathofysiologie, Wilrijk, Belgium
Background

Arterial media calcification (AMC) is a severe complication in patients with chronic kidney disease, diabetes and osteoporosis. In vitro studies showed that the synthetic P2X receptor agonist β,γ-meATP is a potent inhibitor of vascular smooth muscle cell (VSMC) calcification. Here, we aimed to evaluate whether β,γ-meATP prevents the development of AMC in a rat model of warfarin-induced AMC.

Methods

To induce AMC, rats received a diet containing 0.30% warfarin + 0.15% vitK1 throughout the entire study and were subjected to daily i.p. treatments with vehicle (n=10) or 2 mg/kg/day β,γ-meATP (n=10) from start of the study until sacrifice at wk7. Four rats on a standard chow diet were included as a control group. Serum calcium (Ca) and phosphorus (P) levels were analyzed at sacrifice. To evaluate the bone-like switch of VSMCs, aortic mRNA expression of TNAP and SOX9 were analyzed by qPCR. AMC was evaluated by analysis of total Ca content in the arteries and quantification of the area % calcification on Von Kossa stained aortic sections. To determine arterial stiffness, ultrasound-based pulse wave velocity (PWV) was evaluated in the abdominal aorta.

Results

Serum P levels were unchanged in all groups while serum Ca was significantly lower in rats treated with β,γ-meATP vs vehicle group. Exposure to warfarin induced distinct calcification in the aorta and peripheral arteries in vehicle treated rats which led to an increase in PWV score. Interestingly, daily treatment with β,γ-meATP significantly reduced the Ca content in the aorta (mean ± SEM; vehicle 1.49 ± 1.51 mg Ca/g wet tissue vs β,γ-meATP 0.38 ± 0.20 mg Ca/g wet tissue; p<0.05) and peripheral vessels which was further reinforced by a significant (p<0.01) reduction in aortic Von Kossa positive area % vs vehicle group. However, β,γ-meATP did not significantly affect PWV scores. Treatment with β,γ-meATP also did not alter the mRNA expression of bone-like marker genes.

Conclusion

β,γ-meATP significantly decreased AMC in the aorta and peripheral vessels of warfarin exposed rats, however, without affecting the bone-like switch of VSMCs suggesting that β,γ-meATP mediates its inhibitory effects on AMC probably by interfering with the formation of Ca-P crystals via its breakdown product methylene bisphosphonate. Further research will be conducted to evidence this hypothesis.

Funding

  • Government Support - Non-U.S.