Dicer generates a regulatory microRNA network in smooth muscle cells that limits neointima formation during vascular repair
| Autor: | Zhe Zhou, Pallavi Subramanian, Christian Weber, Stefan Offermanns, Maliheh Nazari-Jahantigh, Yuanyuan Wei, Farima Zahedi, Andreas Schober, Jochen Grommes, Sabine Steffens |
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| Přispěvatelé: | Biochemie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Ribonuclease III 0301 basic medicine Neointima Vascular smooth muscle medicine.medical_treatment Myocytes Smooth Muscle Muscle Smooth Vascular Mice 03 medical and health sciences Cellular and Molecular Neuroscience Gene expression microRNA medicine Animals Humans Gene Regulatory Networks RNA Messenger ARHGEF26 Molecular Biology Cell proliferation Pharmacology Regulation of gene expression Wound Healing Messenger RNA biology Gene Expression Profiling Growth factor MicroRNA Arteries Cell Biology musculoskeletal system MicroRNAs HEK293 Cells 030104 developmental biology Gene Expression Regulation Smooth muscle cells Organ Specificity cardiovascular system biology.protein Cancer research Molecular Medicine Female tissues Gene Deletion Rho Guanine Nucleotide Exchange Factors Dicer |
| Zdroj: | Cellular and Molecular Life Sciences, 74(2), 359-372. Springer |
| ISSN: | 1420-682X |
| DOI: | 10.1007/s00018-016-2349-0 |
| Popis: | MicroRNAs (miRNAs) coordinate vascular repair by regulating injury-induced gene expression in vascular smooth muscle cells (SMCs) and promote the transition of SMCs from a contractile to a proliferating phenotype. However, the effect of miRNA expression in SMCs on neointima formation is unclear. Therefore, we studied the role of miRNA biogenesis by Dicer in SMCs in vascular repair. Following wire-induced injury to carotid arteries of Apolipoprotein E knockout (Apoe -/-) mice, miRNA microarray analysis revealed that the most significantly regulated miRNAs, such as miR-222 and miR-21-3p, were upregulated. Conditional deletion of Dicer in SMCs increased neointima formation by reducing SMC proliferation in Apoe -/- mice, and decreased mainly the expression of miRNAs, such as miR-147 and miR-100, which were not upregulated following vascular injury. SMC-specific deletion of Dicer promoted growth factor and inflammatory signaling and regulated a miRNA-target interaction network in injured arteries that was enriched in anti-proliferative miRNAs. The most connected miRNA in this network was miR-27a-3p [e.g., with Rho guanine nucleotide exchange factor 26 (ARHGEF26)], which was expressed in medial and neointimal SMCs in a Dicer-dependent manner. In vitro, miR-27a-3p suppresses ARHGEF26 expression and inhibits SMC proliferation by interacting with a conserved binding site in the 3' untranslated region of ARHGEF26 mRNA. We propose that Dicer expression in SMCs plays an essential role in vascular repair by generating anti-proliferative miRNAs, such as miR-27a-3p, to prevent vessel stenosis due to exaggerated neointima formation. |
| Databáze: | OpenAIRE |
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