The P2Y2 nucleotide receptor is an inhibitor of vascular calcification

Shaomin Qian, Jenna Regan, Maxwell T. Shelton, April Hoggatt, Khalid Mohammad, B. Herring, Cheikh Seye

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background and aims Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y2 receptor (P2Y2R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. Methods Apolipoprotein E, P2Y2R double knockout mice (ApoE−/−P2Y2R−/−) were used to determine the effect of P2Y2R deficiency on vascular calcification in vivo. Vascular smooth muscle cells (VSMC) isolated from P2Y2R−/− mice grown in high phosphate medium were used to assess the role of P2Y2R in the conversion of VSMC into osteoblasts. Luciferase-reporter assays were used to assess the effect of P2Y2R on the transcriptional activity of Runx2. Results P2Y2R deficiency in ApoE−/− mice caused extensive intimal calcification despite a significant reduction in atherosclerosis and macrophage plaque content. The ectoenzyme apyrase that degrades nucleoside di- and triphosphates accelerated high phosphate-induced calcium deposition in cultured VSMC. Expression of P2Y2R inhibits calcification in vitro inhibited the osteoblastic trans-differentiation of VSMC. Mechanistically, expression of P2Y2R inhibited Runx2 transcriptional activation of an osteocalcin promoter driven luciferase reporter gene. Conclusions This study reveals a role for vascular P2Y2R as an inhibitor of arterial intimal calcification and provides a new mechanistic insight into the regulation of the osteoblastic trans-differentiation of SMC through P2Y2R-mediated Runx2 antagonism. Given that calcification of atherosclerotic lesions is a significant clinical problem, activating P2Y2R may be an effective therapeutic approach for treatment or prevention of vascular calcification.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalAtherosclerosis
Volume257
DOIs
StatePublished - Feb 1 2017

Fingerprint

Purinergic P2Y2 Receptors
Vascular Calcification
Nucleotides
Tunica Intima
Vascular Smooth Muscle
Smooth Muscle Myocytes
Low Density Lipoprotein Receptor-Related Protein-1
nucleotidase
Luciferases
Apyrase
Purinergic Receptors
5'-Nucleotidase
Diphosphates
Osteocalcin
Apolipoproteins E
Adenosine Monophosphate
Osteoblasts

Keywords

  • Atherosclerosis
  • ATP
  • Inflammation
  • Nucleotide receptor
  • Vascular calcification

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

The P2Y2 nucleotide receptor is an inhibitor of vascular calcification. / Qian, Shaomin; Regan, Jenna; Shelton, Maxwell T.; Hoggatt, April; Mohammad, Khalid; Herring, B.; Seye, Cheikh.

In: Atherosclerosis, Vol. 257, 01.02.2017, p. 38-46.

Research output: Contribution to journalArticle

Qian, Shaomin ; Regan, Jenna ; Shelton, Maxwell T. ; Hoggatt, April ; Mohammad, Khalid ; Herring, B. ; Seye, Cheikh. / The P2Y2 nucleotide receptor is an inhibitor of vascular calcification. In: Atherosclerosis. 2017 ; Vol. 257. pp. 38-46.
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abstract = "Background and aims Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y2 receptor (P2Y2R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. Methods Apolipoprotein E, P2Y2R double knockout mice (ApoE−/−P2Y2R−/−) were used to determine the effect of P2Y2R deficiency on vascular calcification in vivo. Vascular smooth muscle cells (VSMC) isolated from P2Y2R−/− mice grown in high phosphate medium were used to assess the role of P2Y2R in the conversion of VSMC into osteoblasts. Luciferase-reporter assays were used to assess the effect of P2Y2R on the transcriptional activity of Runx2. Results P2Y2R deficiency in ApoE−/− mice caused extensive intimal calcification despite a significant reduction in atherosclerosis and macrophage plaque content. The ectoenzyme apyrase that degrades nucleoside di- and triphosphates accelerated high phosphate-induced calcium deposition in cultured VSMC. Expression of P2Y2R inhibits calcification in vitro inhibited the osteoblastic trans-differentiation of VSMC. Mechanistically, expression of P2Y2R inhibited Runx2 transcriptional activation of an osteocalcin promoter driven luciferase reporter gene. Conclusions This study reveals a role for vascular P2Y2R as an inhibitor of arterial intimal calcification and provides a new mechanistic insight into the regulation of the osteoblastic trans-differentiation of SMC through P2Y2R-mediated Runx2 antagonism. Given that calcification of atherosclerotic lesions is a significant clinical problem, activating P2Y2R may be an effective therapeutic approach for treatment or prevention of vascular calcification.",
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AU - Qian, Shaomin

AU - Regan, Jenna

AU - Shelton, Maxwell T.

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AU - Mohammad, Khalid

AU - Herring, B.

AU - Seye, Cheikh

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N2 - Background and aims Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y2 receptor (P2Y2R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. Methods Apolipoprotein E, P2Y2R double knockout mice (ApoE−/−P2Y2R−/−) were used to determine the effect of P2Y2R deficiency on vascular calcification in vivo. Vascular smooth muscle cells (VSMC) isolated from P2Y2R−/− mice grown in high phosphate medium were used to assess the role of P2Y2R in the conversion of VSMC into osteoblasts. Luciferase-reporter assays were used to assess the effect of P2Y2R on the transcriptional activity of Runx2. Results P2Y2R deficiency in ApoE−/− mice caused extensive intimal calcification despite a significant reduction in atherosclerosis and macrophage plaque content. The ectoenzyme apyrase that degrades nucleoside di- and triphosphates accelerated high phosphate-induced calcium deposition in cultured VSMC. Expression of P2Y2R inhibits calcification in vitro inhibited the osteoblastic trans-differentiation of VSMC. Mechanistically, expression of P2Y2R inhibited Runx2 transcriptional activation of an osteocalcin promoter driven luciferase reporter gene. Conclusions This study reveals a role for vascular P2Y2R as an inhibitor of arterial intimal calcification and provides a new mechanistic insight into the regulation of the osteoblastic trans-differentiation of SMC through P2Y2R-mediated Runx2 antagonism. Given that calcification of atherosclerotic lesions is a significant clinical problem, activating P2Y2R may be an effective therapeutic approach for treatment or prevention of vascular calcification.

AB - Background and aims Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y2 receptor (P2Y2R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. Methods Apolipoprotein E, P2Y2R double knockout mice (ApoE−/−P2Y2R−/−) were used to determine the effect of P2Y2R deficiency on vascular calcification in vivo. Vascular smooth muscle cells (VSMC) isolated from P2Y2R−/− mice grown in high phosphate medium were used to assess the role of P2Y2R in the conversion of VSMC into osteoblasts. Luciferase-reporter assays were used to assess the effect of P2Y2R on the transcriptional activity of Runx2. Results P2Y2R deficiency in ApoE−/− mice caused extensive intimal calcification despite a significant reduction in atherosclerosis and macrophage plaque content. The ectoenzyme apyrase that degrades nucleoside di- and triphosphates accelerated high phosphate-induced calcium deposition in cultured VSMC. Expression of P2Y2R inhibits calcification in vitro inhibited the osteoblastic trans-differentiation of VSMC. Mechanistically, expression of P2Y2R inhibited Runx2 transcriptional activation of an osteocalcin promoter driven luciferase reporter gene. Conclusions This study reveals a role for vascular P2Y2R as an inhibitor of arterial intimal calcification and provides a new mechanistic insight into the regulation of the osteoblastic trans-differentiation of SMC through P2Y2R-mediated Runx2 antagonism. Given that calcification of atherosclerotic lesions is a significant clinical problem, activating P2Y2R may be an effective therapeutic approach for treatment or prevention of vascular calcification.

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KW - ATP

KW - Inflammation

KW - Nucleotide receptor

KW - Vascular calcification

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