Deletion of P2Y2 receptor reveals a role for lymphotoxin-α in fatty streak formation

Shaomin Qian, April Hoggatt, Yava L. Jones-Hall, Carl F. Ware, B. Herring, Cheikh Seye

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Lymphotoxin alpha (LTα) is expressed in human atherosclerotic lesions and genetic variations in the LTα pathway have been linked to myocardial infarction. Activation of the P2Y2 nucleotide receptor (P2Y2R) regulates the production of LTα. in vitro. We aimed to uncover a potential pathway linking purinergic receptor to LTα-mediated inflammatory processes pivotal to the early stages of atherosclerosis in apolipoprotein E (ApoE- / -) deficient mice. Methods and results: En face immunostaining revealed that P2Y2R and VCAM-1 are preferentially expressed in the atherosclerosis prone site of the mouse aortic sinus. Deletion of the P2Y2R gene suppresses VCAM-1 expression. Compared with ApoE- / - mice, ApoE- / - mice lacking the P2Y2R gene (ApoE- / -/P2Y2R- / -) did not develop fatty streak lesions when fed a standard chow diet for 15weeks. Systemic and CD4+ T cell production of the pro-inflammatory cytokine lymphotoxin-alpha (LTα) were specifically inhibited in ApoE- / -/P2Y2R- / -mice. Anti-LTα preventive treatment was initiated in ApoE- / - mice with intraperitoneal administration of recombinant human tumor necrosis factor receptor 1 fusion protein (TNFR1-Fc) on 5 consecutive days before the disease onset. Remarkably, none of the TNFR1:Fc-treated ApoE- / - mice exhibited atherosclerotic lesions at any developmental stage. Significance: ApoE- / - mice deficient in P2Y2R exhibit low endothelial cell VCAM-1 levels, decreased production of LTα and delayed onset of atherosclerosis. These data suggest that targeting this nucleotide receptor could be an effective therapeutic approach in atherosclerosis.

Original languageEnglish (US)
JournalVascular Pharmacology
DOIs
StateAccepted/In press - Mar 7 2016

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Purinergic P2Y2 Receptors
Lymphotoxin-alpha
Apolipoproteins E
Nucleotides
Vascular Cell Adhesion Molecule-1
Atherosclerosis
Receptors, Tumor Necrosis Factor, Type I
Purinergic Receptors
Sinus of Valsalva
Tumor Necrosis Factor Receptors
Genes
Endothelial Cells
Myocardial Infarction
Cytokines
Diet
T-Lymphocytes

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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Deletion of P2Y2 receptor reveals a role for lymphotoxin-α in fatty streak formation. / Qian, Shaomin; Hoggatt, April; Jones-Hall, Yava L.; Ware, Carl F.; Herring, B.; Seye, Cheikh.

In: Vascular Pharmacology, 07.03.2016.

Research output: Contribution to journalArticle

Qian, Shaomin ; Hoggatt, April ; Jones-Hall, Yava L. ; Ware, Carl F. ; Herring, B. ; Seye, Cheikh. / Deletion of P2Y2 receptor reveals a role for lymphotoxin-α in fatty streak formation. In: Vascular Pharmacology. 2016.
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abstract = "Background: Lymphotoxin alpha (LTα) is expressed in human atherosclerotic lesions and genetic variations in the LTα pathway have been linked to myocardial infarction. Activation of the P2Y2 nucleotide receptor (P2Y2R) regulates the production of LTα. in vitro. We aimed to uncover a potential pathway linking purinergic receptor to LTα-mediated inflammatory processes pivotal to the early stages of atherosclerosis in apolipoprotein E (ApoE- / -) deficient mice. Methods and results: En face immunostaining revealed that P2Y2R and VCAM-1 are preferentially expressed in the atherosclerosis prone site of the mouse aortic sinus. Deletion of the P2Y2R gene suppresses VCAM-1 expression. Compared with ApoE- / - mice, ApoE- / - mice lacking the P2Y2R gene (ApoE- / -/P2Y2R- / -) did not develop fatty streak lesions when fed a standard chow diet for 15weeks. Systemic and CD4+ T cell production of the pro-inflammatory cytokine lymphotoxin-alpha (LTα) were specifically inhibited in ApoE- / -/P2Y2R- / -mice. Anti-LTα preventive treatment was initiated in ApoE- / - mice with intraperitoneal administration of recombinant human tumor necrosis factor receptor 1 fusion protein (TNFR1-Fc) on 5 consecutive days before the disease onset. Remarkably, none of the TNFR1:Fc-treated ApoE- / - mice exhibited atherosclerotic lesions at any developmental stage. Significance: ApoE- / - mice deficient in P2Y2R exhibit low endothelial cell VCAM-1 levels, decreased production of LTα and delayed onset of atherosclerosis. These data suggest that targeting this nucleotide receptor could be an effective therapeutic approach in atherosclerosis.",
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AB - Background: Lymphotoxin alpha (LTα) is expressed in human atherosclerotic lesions and genetic variations in the LTα pathway have been linked to myocardial infarction. Activation of the P2Y2 nucleotide receptor (P2Y2R) regulates the production of LTα. in vitro. We aimed to uncover a potential pathway linking purinergic receptor to LTα-mediated inflammatory processes pivotal to the early stages of atherosclerosis in apolipoprotein E (ApoE- / -) deficient mice. Methods and results: En face immunostaining revealed that P2Y2R and VCAM-1 are preferentially expressed in the atherosclerosis prone site of the mouse aortic sinus. Deletion of the P2Y2R gene suppresses VCAM-1 expression. Compared with ApoE- / - mice, ApoE- / - mice lacking the P2Y2R gene (ApoE- / -/P2Y2R- / -) did not develop fatty streak lesions when fed a standard chow diet for 15weeks. Systemic and CD4+ T cell production of the pro-inflammatory cytokine lymphotoxin-alpha (LTα) were specifically inhibited in ApoE- / -/P2Y2R- / -mice. Anti-LTα preventive treatment was initiated in ApoE- / - mice with intraperitoneal administration of recombinant human tumor necrosis factor receptor 1 fusion protein (TNFR1-Fc) on 5 consecutive days before the disease onset. Remarkably, none of the TNFR1:Fc-treated ApoE- / - mice exhibited atherosclerotic lesions at any developmental stage. Significance: ApoE- / - mice deficient in P2Y2R exhibit low endothelial cell VCAM-1 levels, decreased production of LTα and delayed onset of atherosclerosis. These data suggest that targeting this nucleotide receptor could be an effective therapeutic approach in atherosclerosis.

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