Leptin-induced endothelial dysfunction in obesity
Open accessAbstract
Hyperleptinemia accompanying obesity affects endothelial nitric oxide (NO) and is a serious factor for vascular disorders. NO, superoxide (O 2−), and peroxynitrite (ONOO−) nanosensors were placed near the surface (5 ± 2 μm) of a single human umbilical vein endothelial cell (HUVEC) exposed to leptin or aortic endothelium of obese C57BL/6J mice, and concentrations of calcium ionophore (CaI)-stimulated NO, O 2−, ONOO− were recorded. Endothelial NO synthase (eNOS) expression and l-arginine concentrations in HUVEC and aortic endothelium were measured. Leptin did not directly stimulate NO, O 2−, or ONOO− release from HUVEC. However, a 12-h exposure of HUVEC to leptin increased eNOS expression and CaI-stimulated NO (625 ± 30 vs. 500 ± 24 nmol/l control) and dramatically increased cytotoxic O 2− and ONOO− levels. The [NO]-to-[ONOO−] ratio ([NO]/[ONOO−]) decreased from 2.0 ± 0.1 in normal to 1.30 ± 0.1 in leptin-induced dysfunctional endothelium. In obese mice, a 2.5-fold increase in leptin concentration coincided with 100% increase in eNOS and about 30% decrease in intracellular l-arginine. The increased eNOS expression and a reduced l-arginine content led to eNOS uncoupling, a reduction in bioavailable NO (250 ± 10 vs. 420 ± 12 nmol/l control), and an elevated concentration of O 2− (240%) and ONOO− (70%). l-Arginine and sepiapterin supplementation reversed eNOS uncoupling and partially restored [NO]/[ONOO−] balance in obese mice. In obesity, leptin increases eNOS expression and decreases intracellular l-arginine, resulting in eNOS an uncoupling and depletion of endothelial NO and an increase of cytotoxic ONOO−. Hyperleptinemia triggers an endothelial NO/ONOO− imbalance characteristic of dysfunctional endothelium observed in other vascular disorders, i.e., atherosclerosis and diabetes.
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Metal-thiol bonds are among the main targets of peroxynitrite.
“This observation is not unexpected, as metal-thiol bonds are some of the main targets of peroxynitrite (78, 526).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [526]
Peroxynitrite reacts relatively slowly in comparison with other RNS with many biomolecules, including metal centers, proteins, DNA, and lipids.
“Despite its rapid rate of formation, peroxynitrite reacts relatively slowly in comparison with other RNS, with many biomolecules, including metal centers, proteins, DNA, and lipids (78, 526, 709).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [526]
Reaction of peroxynitrite with Zn/S clusters such as that present in eNOS causes dysfunction of the enzyme.
“Reaction of peroxynitrite with Zn/S clusters such as that present in eNOS, causes dysfunction of the enzyme as outlined above (sect. IIIB3) (78, 526).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [526]
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
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- Authors
- Korda, M., Kubant, R., Patton, S., & Malinski, T.
- Affiliations
- Ohio University (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2008-10
- Volume
- 295
- Issue
- 4
- Pages
- H1514-H1521
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC2593507
- OpenAlex
- W2129275176
- Cited by
- 213
- References
- 36
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 6 · 2023: 10 · 2022: 9 · 2021: 10 · 2020: 11 · 2019: 1 · 2018: 11 · 2017: 8 · 2016: 17 · 2015: 14 · 2014: 24 · 2013: 21 · 2012: 16
- FWCI
- 9.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 55397, R01HL055397)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- leptin, endothelial dysfunction, obesity, hyperleptinemia, endothelial nitric oxide synthase, eNOS uncoupling, nitric oxide, peroxynitrite, superoxide, L-arginine, human umbilical vein endothelial cells, aortic endothelium, vascular dysfunction
- MeSH terms
- Animals, Arginine, Calcium, Disease Models, Animal, Endothelium, Vascular, Enzyme Inhibitors, Humans, Ionophores, Male, Mice, Inbred C57BL, Nitric Oxide, Obesity, Superoxides, Time Factors, Biosensing Techniques, Reactive Oxygen Species, Leptin, Peroxynitrous Acid, Nanotechnology, Endothelial Cells, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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