Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress

Abstract Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcription...

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Autores principales:	Justin M. Quiles, Mark E. Pepin, Sini Sunny, Sandeep B. Shelar, Anil K. Challa, Brian Dalley, John R. Hoidal, Steven M. Pogwizd, Adam R. Wende, Namakkal S. Rajasekaran
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0bacb871034845faa009f27435e581fe
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spelling	oai:doaj.org-article:0bacb871034845faa009f27435e581fe2021-12-02T14:58:14ZIdentification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress10.1038/s41598-021-90583-y2045-2322https://doaj.org/article/0bacb871034845faa009f27435e581fe2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90583-yhttps://doaj.org/toc/2045-2322Abstract Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2 −/−) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. “reductomiRs”) associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these “reductomiRs” as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.Justin M. QuilesMark E. PepinSini SunnySandeep B. ShelarAnil K. ChallaBrian DalleyJohn R. HoidalSteven M. PogwizdAdam R. WendeNamakkal S. RajasekaranNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Justin M. Quiles Mark E. Pepin Sini Sunny Sandeep B. Shelar Anil K. Challa Brian Dalley John R. Hoidal Steven M. Pogwizd Adam R. Wende Namakkal S. Rajasekaran Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
description	Abstract Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2 −/−) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. “reductomiRs”) associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these “reductomiRs” as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.
format	article
author	Justin M. Quiles Mark E. Pepin Sini Sunny Sandeep B. Shelar Anil K. Challa Brian Dalley John R. Hoidal Steven M. Pogwizd Adam R. Wende Namakkal S. Rajasekaran
author_facet	Justin M. Quiles Mark E. Pepin Sini Sunny Sandeep B. Shelar Anil K. Challa Brian Dalley John R. Hoidal Steven M. Pogwizd Adam R. Wende Namakkal S. Rajasekaran
author_sort	Justin M. Quiles
title	Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
title_short	Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
title_full	Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
title_fullStr	Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
title_full_unstemmed	Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
title_sort	identification of nrf2-responsive microrna networks as putative mediators of myocardial reductive stress
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0bacb871034845faa009f27435e581fe
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Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress

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