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
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The NAD(P) + -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.
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In heart, CD38+ cells are mainly FAPs and endothelial cells, with few CD45+ cells.
“the CD38+ cell population in the heart consisted of FAP and endothelial cells with few CD45+ cells represented”
From A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline (2018) · cites this paper as Boslett et al., 2018
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- Authors
- Boslett, J., Hemann, C., Christofi, F. L., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- The Ohio State University Wexner Medical Center (US)
- Corresponding author
- Zweier, Jay L.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2018-03-01
- Volume
- 314
- Issue
- 3
- Pages
- C297-C309
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC6335017
- OpenAlex
- W2769944289
- Cited by
- 65
- References
- 57
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 9 · 2023: 10 · 2022: 12 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 5
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (HL131941, HL135648)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- CD38, endothelial cells, hypoxia/reoxygenation, endothelial dysfunction, cardiomyocytes, cardiac fibroblasts, endothelial nitric oxide synthase, eNOS uncoupling, nitric oxide, superoxide, myocardial ischemia-reperfusion injury
- MeSH terms
- Animals, Coronary Vessels, Enzyme Activation, Fibroblasts, Membrane Glycoproteins, Mice, Inbred C57BL, NADP, Nitric Oxide, Superoxides, Time Factors, Signal Transduction, Myocardial Reperfusion, Myocardial Reperfusion Injury, Cell Hypoxia, Rats, Sprague-Dawley, Mice, Knockout, Myocytes, Cardiac, ADP-ribosyl Cyclase, Endothelial Cells, ADP-ribosyl Cyclase 1, Nitric Oxide Synthase Type III
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