Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide
Open accessAbstract
Endothelial NOS (eNOS)-derived NO has long been considered a paracrine signaling molecule only capable of affecting nearby cells because of its short half-life in blood and relatively limited diffusion distance in tissues. To date, no studies have demonstrated that endogenously generated NO possesses a clearly defined endocrine function. Therefore, we evaluated whether enzymatic generation of NO in the heart is capable of modulating remote physiological actions and cell signaling. Mice with cardiac-specific overexpression of the human eNOS gene (CS-eNOS-Tg) were used to address this hypothesis. Cardiac-specific eNOS overexpression resulted in significant increases in nitrite, nitrate, and nitrosothiols in the heart, plasma, and liver. To examine whether the increase in hepatic NO metabolites could modulate cytoprotection, we subjected CS-eNOS-Tg mice to hepatic ischemia-reperfusion (I/R) injury. CS-eNOS-Tg mice displayed a significant reduction in hepatic I/R injury (4.2-fold reduction in the aminotransferase and a 3.5-fold reduction in aspartate aminotransferase) compared with WT littermates. These findings demonstrate that endogenously derived NO is transported in the blood, metabolized in remote organs, and mediates cytoprotection in the setting of I/R injury. This study presents clear evidence for an endocrine role of NO generated endogenously from eNOS and provides additional evidence for the profound cytoprotective actions of NO in the setting of I/R injury.
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CS-eNOS-Tg mice display significant protection against hepatic I/R injury due to the increase in hepatic NO metabolites originating from the myocardium.
“CS-eNOS-Tg mice displayed a significant protection against hepatic I/R injury due to the increase in hepatic NO metabolites originating from the myocardium.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [164]
CS-eNOS-Tg mice have significant increases in nitrite, nitrate, and nitrosothiols in the heart, plasma, and liver.
“Elrod et al documented significant increases in nitrite, nitrate, and nitrosothiols in the heart, plasma, and liver [164].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [164]
Pharmacological scavengers PTIO and NEM inhibit the protective effects in CS-eNOS-Tg mice, indicating a role for nitrite reduction to NO and S-nitrosylation for cytoprotection.
“Experiments also showed that pharmacological scavengers PTIO and NEM inhibited the protective effects in CS-eNOS-Tg mice, indicating a role for nitrite reduction to NO and S-nitrosylation for cytoprotection [164].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [164]
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- Authors
- Elrod, J. W., Calvert, J. W., Gundewar, S., Bryan, N. S., & Lefer, D. J.
- Affiliations
- Albert Einstein College of Medicine (US)
- Departments of *Medicine and
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-08-12
- Volume
- 105
- Issue
- 32
- Pages
- 11430-11435
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2516252
- OpenAlex
- W2078820537
- Cited by
- 137
- References
- 41
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 8 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 7 · 2016: 4 · 2015: 11 · 2014: 7 · 2013: 15 · 2012: 24
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (2R01 HL-060849, R01HL060849)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK077380)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- nitric oxide, endothelial nitric oxide synthase, hepatic ischemia-reperfusion injury, cytoprotection, nitrite/nitrate, S-nitrosothiols, hepatoprotection
- MeSH terms
- Animals, Biological Transport, Liver, Mice, Transgenic, Myocardium, Nitrates, Nitric Oxide, Nitrites, Organ Specificity, Reperfusion Injury, Cytoprotection, Paracrine Communication, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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