miRNA Therapeutics: A New Class of Drugs with Potential Therapeutic Applications in the Heart

Bernardo, Bianca C.; Ooi, Jenny Y. Y.; Lin, Ruby C.Y.; McMullen, Julie R.

doi:10.4155/fmc.15.107

Cited by 199 publications

(156 citation statements)

References 171 publications

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“…; Bernardo et al . ). Nonetheless, with improvements and developments in delivery tools (including the use of nanoparticles, liposomes and antibodies), miRNA‐based therapies remain a promising approach for the treatment of heart failure (Bernardo et al .…”

Section: Discussionmentioning

confidence: 97%

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Sex differences in response to miRNA‐34a therapy in mouse models of cardiac disease: identification of sex‐, disease‐ and treatment‐regulated miRNAs

Bernardo

Ooi

Matsumoto

et al. 2016

The Journal of Physiology

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MicroRNA (miRNA)-34a (miR-34a) is elevated in the diseased heart in mice and humans. Previous studies have shown that inhibiting miR-34a in male mice in settings of pathological cardiac hypertrophy or ischaemia protects the heart against progression to heart failure. Whether inhibition of miR-34a protects the female heart is unknown. Furthermore, the therapeutic potential of silencing miR-34a in settings of dilated cardiomyopathy (DCM) and atrial fibrillation (AF) has not been assessed previously. In the present study, we examined the effect of silencing miR-34a in males and females in (1) a model of moderate DCM and (2) a model of severe DCM with AF. The cardiac disease models were administered with a locked nucleic acid-modified oligonucleotide (LNA-antimiR-34a) at 6-7 weeks of age when the models display cardiac dysfunction and conduction abnormalities. Cardiac function and morphology were measured 6 weeks after treatment. In the present study, we show that inhibition of miR-34a provides more protection in the DCM model in females than males. Disease prevention in LNA-antimiR-34a treated DCM female mice was characterized by attenuated heart enlargement and lung congestion, lower expression of cardiac stress genes (B-type natriuretic peptide, collagen gene expression), less cardiac fibrosis and better cardiac function. There was no evidence of significant protection in the severe DCM and AF model in either sex. Sex- and treatment-dependent regulation of miRNAs was also identified in the diseased heart, and may explain the differential response of males and females. These studies highlight the importance of examining the impact of miRNA-based drugs in both sexes and under different disease conditions.

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Section: Discussionmentioning

confidence: 97%

“…; Bernardo et al . ). Although sex differences are well recognized in human disease, relatively few studies have specifically examined miRNA sex differences in humans (Sharma & Eghbali, ).…”

Section: Introductionmentioning

confidence: 97%

Sex differences in response to miRNA‐34a therapy in mouse models of cardiac disease: identification of sex‐, disease‐ and treatment‐regulated miRNAs

Bernardo

Ooi

Matsumoto

et al. 2016

The Journal of Physiology

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“…miRNAs participate in the regulation of various biological processes, including cell proliferation, cell cycle progression, and cell survival . There is some evidence to suggest that miRNA expression changed the across different species from miRNAs in many models of myocardial I/R injury, demonstrating the pivotal role of miRNAs in myocardial ischemic injury .…”

Section: Discussionmentioning

confidence: 99%

MiR‐27 alleviates myocardial cell damage induced by hypoxia/reoxygenation via targeting TGFBR1 and inhibiting NF‐κB pathway

Zhang

2019

The Kaohsiung J of Med Scie

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MiR‐27 prevents atherosclerosis by inhibiting inflammatory responses induced by lipoprotein lipase. Overexpression of miR‐27b attenuates angiotensin‐induced atrial fibrosis. Nevertheless, studies have rarely investigated on the effect of miR‐27 in cardiomyocyte injury. H9c2 cells were transfected with miR‐27 mimic/inhibitor. Then the cell proliferation was tested by MTT assay and the cell apoptosis was detected by flow cytometry. The luciferase activity assay was utilized to analyze the relationship between miR‐27 and TGFBR1. Quantificational real‐time polymerase chain reaction and western blot were utilized to detect the cardiomyocyte differentiation marker and nuclear factor kappa B (NF‐κB) pathway. Our outcomes demonstrated that miR‐27 expression was downregulated cardiomyocyte injury subjected to hypoxia/reoxygenation (H/R). Additionally, overexpression of miR‐27 could significantly alleviate cardiomyocyte injury by regulating cell activity and apoptosis. The luciferase activity assay confirmed that transforming growth factor ß receptor 1 (TGFBR1) is a direct hallmark of miR‐27. Besides, overexpression of miR‐27 promoted the expression of TGFBR1 in H/R model. After transfection with miR‐27 mimic/inhibitor, the expression of NF‐κB pathway‐related proteins was decreased/increased. Taken together, our data manifested that miR‐27 repressed cardiomyocyte injury induced by H/R via mediating TGFBR1 and inhibiting NF‐κB signaling pathway. Furthermore, miR‐27/ TGFBR1 might be utilized as hopeful biomarkers for myocardial ischemia diagnosis and treatment.

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“…MicroRNAs (miRNAs), small (approximately 18–24 nucleotides) and endogenous noncoding RNA molecules, regulate gene expression by destabilizing messenger RNA (mRNA) and/or repressing translation (Bernardo, Ooi, Lin, & McMullen, 2015; Meister & Tuschl, 2004). Ample evidence proves miRNAs as key regulators during hepatocarcinogenesis (Giordano & Columbano, 2013).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

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Primary liver cancer is the second most frequent cause of cancer‐related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA‐214‐3p (miR‐214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR‐214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR‐214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre‐miR‐214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti‐miR‐214 sponge showed the opposite effect. Additionally, pre‐miR‐214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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miRNA Therapeutics: A New Class of Drugs with Potential Therapeutic Applications in the Heart

Cited by 199 publications

References 171 publications

Sex differences in response to miRNA‐34a therapy in mouse models of cardiac disease: identification of sex‐, disease‐ and treatment‐regulated miRNAs

Sex differences in response to miRNA‐34a therapy in mouse models of cardiac disease: identification of sex‐, disease‐ and treatment‐regulated miRNAs

MiR‐27 alleviates myocardial cell damage induced by hypoxia/reoxygenation via targeting TGFBR1 and inhibiting NF‐κB pathway

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

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