Parathyroid Hormone Causes Endothelial Dysfunction by Inducing Mitochondrial ROS and Specific Oxidative Signal Transduction Modifications
Open accessAbstract
Vitamin D deficiency contributes to cardiovascular risk (CVR), with hyperparathyroidism advocated as a putative mechanism. Indeed, mounting evidence supports the hypothesis that parathyroid hormone (PTH) impairs endothelial function, even though mechanisms are not fully elucidated. The present study was designed to verify in vitro the ability of sustained exposure to PTH to cause endothelial dysfunction, exploring the underlying mechanisms. In bovine aortic endothelial cells (BAECs), we evaluated the effects of PTH exposure (0.1 nM–24 hours) on both endothelial response to vasodilators, such as bradykinin (Bk (30 nM)) and acetylcholine (Ach (1 μ M)), and angiogenic competence. Pretreatment with PTH impaired endothelial response to Bk but not to Ach, in terms of cytosolic calcium fluxes and NO production. In order to explore the underlying mechanisms, we assessed the production of total and mitochondrial ROS (tROS and mROS, respectively) in response to PTH (at 1 and 3 hours). PTH increased ROS generation, to an extent high enough to determine oxidation of Bk receptor B2. Conversely, the oxidation levels of M1 and M3 Ach receptors were not affected by PTH. A mROS selective scavenger (MitoTEMPO (5 μ M)) restored the endothelial responsiveness to Bk while the well‐known antioxidant properties of vitamin D (100 nM) failed to counteract PTH‐mediated oxidative stress. PTH determined mitochondrial calcium fluxes ([Ca 2+ ] mt ) and the mitochondrial calcium uniporter inhibitor Ru360 (10 μ M) reduced mROS production and prevented the PTH‐mediated endothelial dysfunction. Angiogenic competence was evaluated as tubular formations in the endothelial Matrigel assay and showed a significant impairment in PTH‐pretreated cells (0.1 nM–24 hours), despite the increase in VEGF transcriptional levels. VEGFR2 oxidation occurred in response to PTH, suggesting that even the impairment of angiogenesis was due to the ROS surge. These results indicate that PTH affects endothelial function through ROS production, driven by mitochondrial calcium overload. PTH‐induced oxidative stress might act as signaling modifiers, altering specific pathways (Bk and VEGF) and preserving others (Ach).
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“Медиана возраста – 50,5 года [37,5; 57,5], СКФ – 97,8 мл/мин/1,73 м2 [92,8; 103,1].”
- Authors
- Gambardella, J., De Rosa, M., Sorriento, D., Prevete, N., Fiordelisi, A., Ciccarelli, M., Trimarco, B., De Luca, N., & Iaccarino, G.
- Affiliations
- University of Naples Federico II (IT)
- Federico II University Hospital (IT)
- University of Salerno (IT)
- Corresponding author
- Iaccarino, Guido
- ORCID
- Venue
- Oxidative Medicine and Cellular Longevity
- Publisher
- Wiley
- Published
- 2018-01
- Volume
- 2018
- Issue
- 1
- Pages
- 9582319-9582319
- ISSN
- 1942-0994 (ISSN-L)
- 1942-0900
- PMC
- PMC6313989
- OpenAlex
- W2905315250
- Cited by
- 58
- References
- 56
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 5 · 2023: 7 · 2022: 11 · 2021: 5 · 2020: 9 · 2019: 3
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Campania Bioscience (PON03PE_00060_8)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- parathyroid hormone, endothelial dysfunction, mitochondrial reactive oxygen species, oxidative stress, mitochondrial calcium overload, angiogenesis, nitric oxide production, vitamin D deficiency, cardiovascular risk, hyperparathyroidism, MitoTEMPO, Ru360
- MeSH terms
- Acetylcholine, Animals, Bradykinin, Calcium, Cattle, Mitochondria, Organophosphorus Compounds, Parathyroid Hormone, Piperidines, Vitamin D, Calcium Channels, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Neovascularization, Physiologic, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Endothelial Cells, Receptor, Bradykinin B2
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