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Author Notes:

Address correspondence to: David J. Pinsky, 7240 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109, USA. Phone: 734.936.3500; E-mail: ude.hcimu.dem@yksnipd.

Authorship note: Yogendra Kanthi and Matthew C. Hyman contributed equally to this work.

We thank Sandeep Kumar, Chanwoo Kim, Wakako Takabe, Dorothy Sorenson, and the University of Michigan Cardiovascular Physiology Phenotyping Core, Vector, Imaging, and Hybridoma Cores for expert technical assistance.

Conflict of interest: David J. Pinsky is an inventor on a patent related to CD39 owned by Columbia University that is not currently licensed (USPTO 6867177).

Subjects:

Research Funding:

D.J. Pinsky was supported by grant funding from the NIH (HL127151, NS087147) and the A. Alfred Taubman Medical Research Institute. D.J. Pinsky received additional funding support from the J. Griswold Ruth MD & Margery Hopkins Ruth Professorship.

H. Jo was supported by grant funding from the NIH (HL119798).

Y. Kanthi and N.R. Sutton were supported by training grants from the NIH (T32HL007853).

S.H. Visovatti and S.N. Goonewardena were supported by grant funding from the National Heart, Lung, and Blood Institute of the NIH (K08HL119623 and K08HL123621, respectively).

M.C. Hyman and A.E. Baek were supported in part by predoctoral fellowship grants from the American Heart Association.

The University of Michigan Physiology Phenotyping Core was supported by grant funding from the NIH (OD016502) and the Frankel Cardiovascular Center.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • KRUPPEL-LIKE FACTOR-2
  • ENDOTHELIAL-CELLS
  • SHEAR-STRESS
  • ATP-DIPHOSPHOHYDROLASE
  • CAROTID BIFURCATION
  • DISTURBED FLOW
  • APYRASE CD39
  • MOUSE
  • INFLAMMATION
  • ACTIVATION

Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis

Tools:

Journal Title:

Journal of Clinical Investigation

Volume:

Volume 125, Number 8

Publisher:

, Pages 3027-3036

Type of Work:

Article | Final Publisher PDF

Abstract:

The ability of cells to detect and respond to nucleotide signals in the local microenvironment is essential for vascular homeostasis. The enzyme ectonucleotide tri(di)phosphohydrolase-1 (ENTPD1, also known as CD39) on the surface of leukocytes and endothelial cells metabolizes locally released, intravascular ATP and ADP, thereby eliminating these prothrombotic and proinflammatory stimuli. Here, we evaluated the contribution of CD39 to atherogenesis in the apolipoprotein E–deficient (ApoE-deficient) mouse model of atherosclerosis. Compared with control ApoE-deficient animals, plaque burden was markedly increased along with circulating markers of platelet activation in Cd39+/–Apoe–/– mice fed a high-fat diet. Plaque analysis revealed stark regionalization of endothelial CD39 expression and function in Apoe–/– mice, with CD39 prominently expressed in atheroprotective, stable flow regions and diminished in atheroprone areas subject to disturbed flow. In mice, disturbed flow as the result of partial carotid artery ligation rapidly suppressed endothelial CD39 expression. Moreover, unidirectional laminar shear stress induced atheroprotective CD39 expression in human endothelial cells. CD39 induction was dependent upon the vascular transcription factor Krüppel-like factor 2 (KLF2) binding near the transcriptional start site of CD39. Together, these data establish CD39 as a regionalized regulator of atherogenesis that is driven by shear stress.

Copyright information:

© 2015, American Society for Clinical Investigation

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