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Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [miRNA]

ABSTRACT: Background: Although modern advances in the treatment of heart disease have reduced mortality rates, long-term medical management is often associated with a progressive loss of function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, a.k.a. Nrf2) is a transcriptional regulator that provides the ischemic heart with transient cytoprotection following acute myocardial insult; however, its sustained activation paradoxically causes reductive stress, an emerging pathological phenomenon characterized by excessive antioxidant function and proteotoxic remodeling. Yet, the molecular mechanism by which chronic reductive stress produces heart failure remains elusive. Methods: Cardiac-specific constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing the transgene at low (TgL) and high (TgH) levels were employed in integrative mRNA and small RNA (miRNA) sequencing. Results and Conclusion: Here, we reveal several Nrf2 dose-responsive miRNA loci harboring putative upstream antioxidant response elements (AREs). Intriguingly, Nrf2-mediated miRNA responses were distinctly enriched for post-transcriptional regulation of cardiac-specific mRNAs. Altogether, these data reveal Nrf2 as a potent regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation into the relationship between myocardial redox status and pathophysiology.

ORGANISM(S): Mus musculus

PROVIDER: GSE120088 | GEO | 2020/04/01

REPOSITORIES: GEO

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Project description:Heart failure is associated with high morbidity and mortality and its incidence increases worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage heart failure before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small-RNA-sequencing. MiRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNAM-bM-^@M-^Starget-mRNA interactions, target mRNA levels were negatively correlated to changes in abundance for highly expressed miRNAs in heart failure and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced heart failure, which coincided with a similar increase in cardiac troponin I protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 months following initiation of LVAD support. In stable heart failure, circulating miRNAs showed less than 5-fold differences compared to normal, and myomir and cardiac troponin I levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers. Total RNA isolated from human left ventricular myocardium of failing hearts due to dilated or ischemic cardiomyopathy before and after mechanical unloading by a left ventricular assist device, and fetal myocardium compared to non-failing postnatal myocardium was subjected to multiplexed small RNA-sequencing on the Illumina platform. mRNA gene expression data using Illumina HumanHT-12v4 beadarrays for a subset of the myocardial samples is available (GSE52601).

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Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [miRNA]

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