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Nrf2 deficiency unmasks the significance of nitric oxide synthase activity for cardioprotection

Nrf2 deficiency unmasks the significance of nitric oxide synthase activity for cardioprotection
Nrf2 deficiency unmasks the significance of nitric oxide synthase activity for cardioprotection

The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch that controls the expression of antioxidant and cytoprotective enzymes, including enzymes catalyzing glutathione de novo synthesis. In this study, we aimed to analyze whether Nrf2 deficiency influences antioxidative capacity, redox state, NO metabolites, and outcome of myocardial ischemia reperfusion (I/R) injury. In Nrf2 knockout (Nrf2 KO) mice, we found elevated eNOS expression and preserved NO metabolite concentrations in the aorta and heart as compared to wild types (WT). Unexpectedly, Nrf2 KO mice have a smaller infarct size following myocardial ischemia/reperfusion injury than WT mice and show fully preserved left ventricular systolic function. Inhibition of NO synthesis at onset of ischemia and during early reperfusion increased myocardial damage and systolic dysfunction in Nrf2 KO mice, but not in WT mice. Consistent with this, infarct size and diastolic function were unaffected in eNOS knockout (eNOS KO) mice after ischemia/reperfusion. Taken together, these data suggest that eNOS upregulation under conditions of decreased antioxidant capacity might play an important role in cardioprotection against I/R. Due to the redundancy in cytoprotective mechanisms, this fundamental antioxidant property of eNOS is not evident upon acute NOS inhibition in WT mice or in eNOS KO mice until Nrf2-related signaling is abrogated.

Journal Article
1942-0900
1-16
Erkens, Ralf
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Suvorava, Tatsiana
94b506fa-15b0-4f1d-9310-b8d2e6c1cb07
Sutton, Thomas R.
dbc4cb4f-cab0-46ee-b911-8945f50563cd
Fernandez, Bernadette O
9890aabc-1fe6-4530-a51e-31182e537131
Mikus-Lelinska, Monika
6ca48669-ff8f-4ae8-9d10-98c74327b4ec
Barbarino, Frederik
b53ad146-43db-4a6e-8038-59fd1033ab0d
Flögel, Ulrich
6ea23db8-d188-4dc7-aac1-6e5d0d25ba85
Kelm, Malte
db2bb062-32d7-4b50-9f65-8ba89ffa5f42
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Cortese-Krott, Miriam M
7dc9b44c-847c-4196-8866-a3cc0c1dc357
Erkens, Ralf
368017ee-ee28-4125-9f43-a16451aa3fbe
Suvorava, Tatsiana
94b506fa-15b0-4f1d-9310-b8d2e6c1cb07
Sutton, Thomas R.
dbc4cb4f-cab0-46ee-b911-8945f50563cd
Fernandez, Bernadette O
9890aabc-1fe6-4530-a51e-31182e537131
Mikus-Lelinska, Monika
6ca48669-ff8f-4ae8-9d10-98c74327b4ec
Barbarino, Frederik
b53ad146-43db-4a6e-8038-59fd1033ab0d
Flögel, Ulrich
6ea23db8-d188-4dc7-aac1-6e5d0d25ba85
Kelm, Malte
db2bb062-32d7-4b50-9f65-8ba89ffa5f42
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Cortese-Krott, Miriam M
7dc9b44c-847c-4196-8866-a3cc0c1dc357

Erkens, Ralf, Suvorava, Tatsiana, Sutton, Thomas R., Fernandez, Bernadette O, Mikus-Lelinska, Monika, Barbarino, Frederik, Flögel, Ulrich, Kelm, Malte, Feelisch, Martin and Cortese-Krott, Miriam M (2018) Nrf2 deficiency unmasks the significance of nitric oxide synthase activity for cardioprotection. Oxidative Medicine and Cellular Longevity, 2018, 1-16. (doi:10.1155/2018/8309698).

Record type: Article

Abstract

The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch that controls the expression of antioxidant and cytoprotective enzymes, including enzymes catalyzing glutathione de novo synthesis. In this study, we aimed to analyze whether Nrf2 deficiency influences antioxidative capacity, redox state, NO metabolites, and outcome of myocardial ischemia reperfusion (I/R) injury. In Nrf2 knockout (Nrf2 KO) mice, we found elevated eNOS expression and preserved NO metabolite concentrations in the aorta and heart as compared to wild types (WT). Unexpectedly, Nrf2 KO mice have a smaller infarct size following myocardial ischemia/reperfusion injury than WT mice and show fully preserved left ventricular systolic function. Inhibition of NO synthesis at onset of ischemia and during early reperfusion increased myocardial damage and systolic dysfunction in Nrf2 KO mice, but not in WT mice. Consistent with this, infarct size and diastolic function were unaffected in eNOS knockout (eNOS KO) mice after ischemia/reperfusion. Taken together, these data suggest that eNOS upregulation under conditions of decreased antioxidant capacity might play an important role in cardioprotection against I/R. Due to the redundancy in cytoprotective mechanisms, this fundamental antioxidant property of eNOS is not evident upon acute NOS inhibition in WT mice or in eNOS KO mice until Nrf2-related signaling is abrogated.

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8309698 - Version of Record
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More information

Accepted/In Press date: 27 February 2018
e-pub ahead of print date: 30 April 2018
Published date: 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 422436
URI: https://eprints.soton.ac.uk/id/eprint/422436
ISSN: 1942-0900
PURE UUID: 84a17331-755a-44c2-8ef7-61ea19ba6cf3
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 24 Jul 2018 16:30
Last modified: 14 Mar 2019 01:36

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