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Characterization of CD38 in the major cell types of the heart: endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2018 Mar 01; Vol. 314 (3), pp. C297-C309. Date of Electronic Publication: 2017 Nov 29. - Publication Year :
- 2018
-
Abstract
- The NAD(P) <superscript>+</superscript> -hydrolyzing enzyme CD38 is activated in the heart during the process of ischemia and reperfusion, triggering NAD(P)(H) depletion. However, the presence and role of CD38 in the major cell types of the heart are unknown. Therefore, we characterize the presence and function of CD38 in cardiac myocytes, endothelial cells, and fibroblasts. To comprehensively evaluate CD38 in these cells, we measured gene transcription via mRNA, as well as protein expression and enzymatic activity. Endothelial cells strongly expressed CD38, while only low expression was present in cardiac myocytes with intermediate levels in fibroblasts. In view of this high level expression in endothelial cells and the proposed role of CD38 in the pathogenesis of endothelial dysfunction, endothelial cells were subjected to hypoxia-reoxygenation to characterize the effect of this stress on CD38 expression and activity. An activity-based CD38 imaging method and CD38 activity assays were used to characterize CD38 activity in normoxic and hypoxic-reoxygenated endothelial cells, with marked CD38 activation seen following hypoxia-reoxygenation. To test the impact of hypoxia-reoxygenation-induced CD38 activation on endothelial cells, NAD(P)(H) levels and endothelial nitric oxide synthase (eNOS)-derived NO production were measured. Marked NADP(H) depletion with loss of NO and increase in superoxide production occurred following hypoxia-reoxygenation that was prevented by CD38 inhibition or knockdown. Thus, endothelial cells have high expression of CD38 which is activated by hypoxia-reoxygenation triggering CD38-mediated NADP(H) depletion with loss of eNOS-mediated NO generation and increased eNOS uncoupling. This demonstrates the importance of CD38 in the endothelium and explains the basis by which CD38 triggers post-ischemic endothelial dysfunction.
- Subjects :
- ADP-ribosyl Cyclase 1 deficiency
ADP-ribosyl Cyclase 1 genetics
Animals
Cell Hypoxia
Coronary Vessels pathology
Endothelial Cells pathology
Enzyme Activation
Fibroblasts metabolism
Membrane Glycoproteins deficiency
Membrane Glycoproteins genetics
Mice, Inbred C57BL
Mice, Knockout
Myocardial Reperfusion Injury genetics
Myocytes, Cardiac enzymology
Nitric Oxide metabolism
Nitric Oxide Synthase Type III metabolism
Rats, Sprague-Dawley
Signal Transduction
Superoxides metabolism
Time Factors
ADP-ribosyl Cyclase metabolism
ADP-ribosyl Cyclase 1 metabolism
Coronary Vessels enzymology
Endothelial Cells enzymology
Membrane Glycoproteins metabolism
Myocardial Reperfusion adverse effects
Myocardial Reperfusion Injury enzymology
NADP metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1563
- Volume :
- 314
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 29187364
- Full Text :
- https://doi.org/10.1152/ajpcell.00139.2017