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Fibrillin-1-regulated miR-122 has a critical role in thoracic aortic aneurysm formation

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Abstract

Thoracic aortic aneurysms (TAA) in Marfan syndrome, caused by fibrillin-1 mutations, are characterized by elevated cytokines and fragmentated elastic laminae in the aortic wall. This study explored whether and how specific fibrillin-1-regulated miRNAs mediate inflammatory cytokine expression and elastic laminae degradation in TAA. miRNA expression profiling at early and late TAA stages using a severe Marfan mouse model (Fbn1mgR/mgR) revealed a spectrum of differentially regulated miRNAs. Bioinformatic analyses predicted the involvement of these miRNAs in inflammatory and extracellular matrix-related pathways. We demonstrate that upregulation of pro-inflammatory cytokines and matrix metalloproteinases is a common characteristic of mouse and human TAA tissues. miR-122, the most downregulated miRNA in the aortae of 10-week-old Fbn1mgR/mgR mice, post-transcriptionally upregulated CCL2, IL-1β and MMP12. Similar data were obtained at 70 weeks of age using Fbn1C1041G/+ mice. Deficient fibrillin-1–smooth muscle cell interaction suppressed miR-122 levels. The marker for tissue hypoxia HIF-1α was upregulated in the aortic wall of Fbn1mgR/mgR mice, and miR-122 was reduced under hypoxic conditions in cell and organ cultures. Reduced miR-122 was partially rescued by HIF-1α inhibitors, digoxin and 2-methoxyestradiol in aortic smooth muscle cells. Digoxin-treated Fbn1mgR/mgR mice demonstrated elevated miR-122 and suppressed CCL2 and MMP12 levels in the ascending aortae, with reduced elastin fragmentation and aortic dilation. In summary, this study demonstrates that miR-122 in the aortic wall inhibits inflammatory responses and matrix remodeling, which is suppressed by deficient fibrillin-1–cell interaction and hypoxia in TAA.

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Data availability

The microarray data have been deposited in the NCBI's Gene Expression Omnibus database https://www.ncbi.nlm.nih.gov/geo and are accessible through GEO Series accession number GSE199285. All other data sets of this study will be made available upon request to the corresponding author.

Abbreviations

AAA:

Abdominal aortic aneurysm

DMSO:

Dimethyl sulfoxide

ECM:

Extracellular matrix

FAK:

Focal adhesion kinase

FBS:

Fetal bovine serum

GSEA:

Gene set enrichment analyses

HIF-1α:

Hypoxia-inducible factor 1α

MFS:

Marfan syndrome

miRNA:

MicroRNA

MMP:

Matrix metalloproteinase

PBS:

Phosphate-buffered saline

PSG:

Penicillin–streptomycin–glutamine

TAA:

Thoracic aortic aneurysm

TGF-β:

Transforming growth factor β

αSMA:

α-Smooth muscle actin

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Acknowledgements

We thank Dr. Francesco Ramirez in the Department of Pharmacological Sciences, Icahn School of Medicine at Mt Sinai for generously providing Fbn1mgR/+ mice. We are grateful to Dr. Jean-Martin Laberge at the Montreal Children’s Hospital for enabling fibroblast collections from donors. We also thank Dr. Anie Philip for providing primary fibroblast controls, and Dr. Ling Li for help with tissue preparations.

Funding

This work was supported by the Canadian Institutes of Health Research (PJT-162099), the Marfan Foundation (USA), The Natural Sciences and Engineering Research Council of Canada (RGPIN-06278), the Genetic Aortic Disorders Association Canada, and the China Scholarship Council.

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Authors and Affiliations

  1. Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada

    Rong-Mo Zhang, Muthu L. Muthu, Neha E. H. Dinesh & Dieter P. Reinhardt

  2. Shriners Hospital for Children-Canada, Montreal, Canada

    Kerstin Tiedemann & Svetlana Komarova

  3. Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada

    Kerstin Tiedemann, Svetlana Komarova & Dieter P. Reinhardt

  4. Department of Surgery, New York University School of Medicine, New York, USA

    Bhama Ramkhelawon

  5. Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada

    Dieter P. Reinhardt

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  1. Rong-Mo Zhang
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  2. Kerstin Tiedemann
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  3. Muthu L. Muthu
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  4. Neha E. H. Dinesh
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  7. Dieter P. Reinhardt
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Contributions

Study conception and design: RMZ, DPR. Acquisition of data: RMZ, KT, BR, MLM, SK. Analysis and interpretation of data: RMZ, DPR. Manuscript writing: RMZ, DPR. Manuscript editing: KT, BR, SK, MLM, NEHD.

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Correspondence to Dieter P. Reinhardt.

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Zhang, RM., Tiedemann, K., Muthu, M.L. et al. Fibrillin-1-regulated miR-122 has a critical role in thoracic aortic aneurysm formation. Cell. Mol. Life Sci. 79, 314 (2022). https://doi.org/10.1007/s00018-022-04337-8

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  • DOI: https://doi.org/10.1007/s00018-022-04337-8

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