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CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation

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Abstract

Cluster of differentiation 73 (CD73) is an ecto-5′ nucleotidase which catalyzes the conversion of AMP to adenosine. One of the many functions of adenosine is to suppress the activity of tissue nonspecific alkaline phosphatase (TNAP), an enzyme important in regulating intracellular calcification. Since myocardial calcification is associated with various cardiac disease states, we studied the individual roles and crosstalk between CD73 and TNAP in regulating myocyte responses to the α1 adrenoceptor agonist phenylephrine in terms of calcification and hypertrophy. Cultured neonatal rat cardiomyocytes were treated with 10 µM phenylephrine for 24 h in the absence or presence of the stable adenosine analog 2-chloro-adenosine, the TNAP inhibitor tetramisole or the CD73 inhibitor α,β-methylene ADP. Phenylephrine produced marked hypertrophy as evidenced by significant increases in myocyte surface area and ANP gene expression, as well as calcification determined by Alizarin Red S staining. These responses were associated with reduced CD73 gene and protein expression and CD73 activity. Conversely, TNAP expression and activity were significantly increased although both were suppressed by 2-chloro-adenosine. CD73 inhibition alone significantly reduced myocyte-derived adenosine levels by >50 %, and directly induced hypertrophy and calcification in the absence of phenylephrine. These responses and those to phenylephrine were abrogated by TNAP inhibition. We conclude that TNAP contributes to the hypertrophic effect of phenylephrine, as well as its ability to produce cardiomyocyte calcification. These responses are minimized by CD73-dependent endogenously produced adenosine.

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Acknowledgments

This work was supported by a grant from the Heart and Stroke Foundation of Ontario (NA 6028). M Karmazyn holds a Tier 1 Canada Research Chair in Experimental Cardiology.

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Author notes

  1. Seiichi Taniai

    Present address: Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, 181-8611, Japan

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada

    Xiaohong Tracey Gan, Seiichi Taniai, Ganjian Zhao, Cathy X. Huang, Thomas J. Velenosi, Jenny Xue, Bradley L. Urquhart & Morris Karmazyn

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  1. Xiaohong Tracey Gan
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Correspondence to Morris Karmazyn.

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Gan, X.T., Taniai, S., Zhao, G. et al. CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation. Mol Cell Biochem 394, 237–246 (2014). https://doi.org/10.1007/s11010-014-2100-9

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  • DOI: https://doi.org/10.1007/s11010-014-2100-9

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