Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 8, Pages 3027-3036Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI79514
Keywords
-
Categories
Funding
- NIH [HL127151, NS087147, HL119798, T32HL007853, OD016502]
- A. Alfred Taubman Medical Research Institute
- J. Griswold Ruth MD & Margery Hopkins Ruth Professorship
- National Heart, Lung, and Blood Institute of the NIH [K08HL119623, K08HL123621]
- American Heart Association
- Frankel Cardiovascular Center
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K08HL123621, T32HL007853, R01HL119798, P01HL095070, K23HL119623, R01HL127151] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS087147] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [K26OD016502] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 Kruppel-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available