Cited by 137Nitric Oxide and Endothelin EffectsCardiac Ischemia and ReperfusionOrgan Transplantation Techniques and Outcomes

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Nitric oxide promotes distant organ protection: Evidence for an endocrine role of nitric oxide

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Elrod, John W., Calvert, John W., Gundewar, Susheel, Bryan, Nathan S., Lefer, David J.·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0800700105PMC PMC2516252

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Abstract

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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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)
ORCID: Elrod, John W.
Calvert, John W.
Bryan, Nathan S.
Lefer, David J.
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
DOI: 10.1073/pnas.0800700105
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 (medical) › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Cardiology and Cardiovascular 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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Nitric oxide promotes distant organ protection: Evidence for an endocrine role of nitric oxide

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