Zahedi, Farima (2017): Role of Dicer in smooth muscle cells during neointima formation. Dissertation, LMU München: Faculty of Medicine |
Preview |
PDF
Zahedi_Farima.pdf 3MB |
Abstract
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-injured 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, like 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.
Item Type: | Theses (Dissertation, LMU Munich) |
---|---|
Keywords: | microRNA; Dicer; smooth muscle cells; cell proliferation; ARHGEF26 |
Subjects: | 600 Technology, Medicine 600 Technology, Medicine > 610 Medical sciences and medicine |
Faculties: | Faculty of Medicine |
Language: | English |
Date of oral examination: | 9. May 2017 |
1. Referee: | Steffens, Sabine |
MD5 Checksum of the PDF-file: | d578680bdb371ad2e7a85e2627bb0483 |
Signature of the printed copy: | 0700/UMD 17413 |
ID Code: | 20767 |
Deposited On: | 24. May 2017 14:14 |
Last Modified: | 23. Oct 2020 19:13 |