MicroRNAs as therapeutic targets in cardiovascular disease

Laggerbauer, Bernhard; Engelhardt, Stefan

doi:10.1172/jci159179

Cited by 91 publications

(80 citation statements)

References 206 publications

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“…Given miR-34 and other miRNAs are ubiquitously expressed, it will be important to target organs or cell types specifically, for example with antibody or vector-based approaches [12,73]. The application of LNA-based antimiR therapies in preclinical animal models has been established in multiple disease settings [74][75][76], and recently in a setting of diabetesinduced heart disease and cardiac dysfunction [77]. Several studies have demonstrated efficacy and safe use of LNA-based antimiR therapies in human clinical trials, including miravisen (targeting the liver expressed miR-122 for the treatment of hepatitis C [13]), In previous work from us and other investigators, it had been shown that inhibiting miR-34a provided cardiac protection in settings of moderate cardiac pathology including aging [23], a model of moderate pressure overload-induced hypertrophy [18], acute myocardial infarction [23], and dilated cardiomyopathy [21].…”

Section: Discussionmentioning

confidence: 99%

“…The application of LNA-based antimiR therapies in preclinical animal models has been established in multiple disease settings [74][75][76], and recently in a setting of diabetesinduced heart disease and cardiac dysfunction [77]. Several studies have demonstrated efficacy and safe use of LNA-based antimiR therapies in human clinical trials, including miravisen (targeting the liver expressed miR-122 for the treatment of hepatitis C [13]), cobomarsen (an inhibitor of miR-155 in patients with T-cell lymphoma [78]), and MRG-110 (an inhibitor of miR-92a-3p, which is known to have a role in cardiovascular disease and wound healing [79]).…”

Section: Discussionmentioning

confidence: 99%

“…However, delivery of LNA-antimiRs to the heart still poses some challenges. Further strategies to specificity, uptake and targeted delivery of antimiR therapies will be required [76,80,81]. One emerging technology to deliver miRNA inhibitors to heart tissue is the use of ultrasound and a microbubble-targeted delivery system [82].…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function

Bernardo

Yildiz

Kiriazis

et al. 2022

Cells

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MicroRNA 34a (miR-34a) is elevated in the heart in a setting of cardiac stress or pathology, and we previously reported that inhibition of miR-34a in vivo provided protection in a setting of pressure overload-induced pathological cardiac hypertrophy and dilated cardiomyopathy. Prior work had also shown that circulating or cardiac miR-34a was elevated in a setting of diabetes. However, the therapeutic potential of inhibiting miR-34a in vivo in the diabetic heart had not been assessed. In the current study, type 1 diabetes was induced in adult male mice with 5 daily injections of streptozotocin (STZ). At 8 weeks post-STZ, when mice had established type 1 diabetes and diastolic dysfunction, mice were administered locked nucleic acid (LNA)-antimiR-34a or saline-control with an eight-week follow-up. Cardiac function, cardiac morphology, cardiac fibrosis, capillary density and gene expression were assessed. Diabetic mice presented with high blood glucose, elevated liver and kidney weights, diastolic dysfunction, mild cardiac enlargement, cardiac fibrosis and reduced myocardial capillary density. miR-34a was elevated in the heart of diabetic mice in comparison to non-diabetic mice. Inhibition of miR-34a had no significant effect on diastolic function or atrial enlargement, but had a mild effect on preventing an elevation in cardiac enlargement, fibrosis and ventricular gene expression of B-type natriuretic peptide (BNP) and the anti-angiogenic miRNA (miR-92a). A miR-34a target, vinculin, was inversely correlated with miR-34a expression, but other miR-34a targets were unchanged. In summary, inhibition of miR-34a provided limited protection in a mouse model with established type 1 diabetes-induced cardiomyopathy and failed to improve diastolic function. Given diabetes represents a systemic disorder with numerous miRNAs dysregulated in the diabetic heart, as well as other organs, strategies targeting multiple miRNAs and/or earlier intervention is likely to be required.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function

Bernardo

Yildiz

Kiriazis

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…There is plentiful evidence suggesting that miRNAs regulate cardiac homeostasis and thus may serve as a diagnostic tool and/or therapeutic target [ 21 ]. Several miRNAs targeting mRNA-encoding proteins involved in cardiac fibrosis are currently being assessed for their potential use as therapeutic targets, but these approaches are still at an early stage [ 22 ]. Therefore, more information is needed to decipher the complicated interactions between miRNAs and the local environment.…”

Section: Discussionmentioning

confidence: 99%

miR-31-5p-Modified RAW 264.7 Macrophages Affect Profibrotic Phenotype of Lymphatic Endothelial Cells In Vitro

Moskalik

Ratajska

Majchrzak

et al. 2022

IJMS

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Cardiac lymphatic vessel (LyV) remodeling as a contributor to heart failure has not been extensively evaluated in metabolic syndrome (MetS). Our studies have shown structural changes in cardiac LyV in MetS that contribute to the development of edema and lead to myocardial fibrosis. Tissue macrophages may affect LyV via secretion of various substances, including noncoding RNAs. The aim of the study was to evaluate the influence of macrophages modified by miR-31-5p, a molecule that regulates fibrosis and lymphangiogenesis, on lymphatic endothelial cells (LECs) in vitro. The experiments were carried out on the RAW 264.7 macrophage cell line and primary dermal lymphatic endothelial cells. RAW 264.7 macrophages were transfected with miR-31-5p and supernatant from this culture was used for LEC stimulation. mRNA expression levels for genes associated with lymphangiogenesis and fibrosis were measured with qRT-PCR. Selected results were confirmed with ELISA or Western blotting. miR-31-5p-modified RAW 264.7 macrophages secreted increased amounts of VEGF-C and TGF-β and a decreased amount of IGF-1. The supernatant from miR-31-5p-modified RAW 264.7 downregulated the mRNA expression for genes regulating endothelial-to-mesenchymal transition (EndoMT) and fibrosis in LECs. Our results suggest that macrophages under the influence of miR-31-5p show the potential to inhibit LEC-dependent fibrosis. However, more studies are needed to confirm this effect in vivo.

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“…The therapeutic potential of miRNAs is based on the knowledge of specific miRNA families involved in several biological processes [10] that are dysregulated in different pathologies, such as cardiovascular diseases [11][12][13][14][15], viral infections [16,17], metabolic diseases [18], diabetes [19], stress-related diseases [20][21][22] and cancer [23]. For this reason, it is conceivable that a molecular therapy takes advantage of their use.…”

Section: Introductionmentioning

confidence: 99%

Next RNA Therapeutics: The Mine of Non-Coding

Garbo

Maione

Tripodi

et al. 2022

IJMS

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The growing knowledge on several classes of non-coding RNAs (ncRNAs) and their different functional roles has aroused great interest in the scientific community. Beyond the Central Dogma of Biology, it is clearly known that not all RNAs code for protein products, and they exert a broader repertoire of biological functions. As described in this review, ncRNAs participate in gene expression regulation both at transcriptional and post-transcriptional levels and represent critical elements driving and controlling pathophysiological processes in multicellular organisms. For this reason, in recent years, a great boost was given to ncRNA-based strategies with potential therapeutic abilities, and nowadays, the use of RNA molecules is experimentally validated and actually exploited in clinics to counteract several diseases. In this review, we summarize the principal classes of therapeutic ncRNA molecules that are potentially implied in disease onset and progression, which are already used in clinics or under clinical trials, highlighting the advantages and the need for a targeted therapeutic strategy design. Furthermore, we discuss the benefits and the limits of RNA therapeutics and the ongoing development of delivery strategies to limit the off-target effects and to increase the translational application.

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MicroRNAs as therapeutic targets in cardiovascular disease

Cited by 91 publications

References 206 publications

In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function

In Vivo Inhibition of miR-34a Modestly Limits Cardiac Enlargement and Fibrosis in a Mouse Model with Established Type 1 Diabetes-Induced Cardiomyopathy, but Does Not Improve Diastolic Function

miR-31-5p-Modified RAW 264.7 Macrophages Affect Profibrotic Phenotype of Lymphatic Endothelial Cells In Vitro

Next RNA Therapeutics: The Mine of Non-Coding

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