Abstract
DiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded-RNA-binding protein, participates in the miRNA biogenesis pathway and contributes to miRNA maturation by interacting with the RNAase III enzyme Drosha in cell nuclei. To investigate the role of DGCR8 in vascular smooth muscle cells (VSMCs) at the postnatal stages, we generated tamoxifen-inducible VSMC specific knockout (iKO) mice by crossing DGCR8loxp/loxp with VSMC specific tamoxifen-inducible Cre transgenic mice SMA-Cre-ERT2. DGCR8iKO mice display reduced body weight one month following tamoxifen treatment and died around 3 months. Blood pressure and vascular reactivity were significantly reduced in DGCR8iKO mice compared to control. Furthermore, loss of DGCR8 in VSMCs inhibited cell proliferation, migration and neointima formation. VSMC differentiation marker genes, including SMA and SM22, were downregulated in DGCR8 iKO mice. The majority of miRNAs were downregulated in DGCR8iKO mice. Disruption of the DGCR8-mediated miRNA biogenesis pathway attenuated multiple signaling pathways including ERK1/2 and AKT. Our results demonstrate that the DGCR8-mediated miRNA pathway is required for maintaining blood pressure, vascular reactivity and vascular wall remodeling at the postnatal stages.
Highlights
IntroductionDiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded RNA binding protein, participates in the miRNA biogenesis pathway by interacting with the RNase III enzyme Drosha and forming a microprocessor in the cell nucleus that processes primary miRNA (pri-miRNA) into precursor miRNA (pre-miRNA)[1,2,3]
DiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded RNA binding protein, participates in the miRNA biogenesis pathway by interacting with the RNase III enzyme Drosha and forming a microprocessor in the cell nucleus that processes primary miRNA into precursor miRNA[1,2,3]
DGCR8iKO mice displayed significantly reduced blood pressure including systolic (A), diastolic (B) and mean (C) compared to controls (N = 5 per group, *p < 0.05). (D) DGCR8iKO mice didn’t display significant differences in heart rate compared to controls. (E and F) The vascular reactivity was measured in thoracic aorta isolated from DGCR8iKO and control mice using a wire myography
Summary
DiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded RNA binding protein, participates in the miRNA biogenesis pathway by interacting with the RNase III enzyme Drosha and forming a microprocessor in the cell nucleus that processes primary miRNA (pri-miRNA) into precursor miRNA (pre-miRNA)[1,2,3]. MiR-195, miR-143/145, and miR-133 were identified and characterized as regulating the VSMC phenotypic switch[9,10,11] These studies indicate that miRNAs may play different roles in contributing to VSMC functions by regulating VSMC proliferation, migration, and differentiation. Since DGCR8cKO mice display a more severe phenotype than that of Drosha or Dicer cKO, the DGCR8-dependent miRNA biogenesis pathway may play a more important role than Drosha or Dicer in regulating VSMC function[13,14]. To further address how DGCR8-dependent miRNA biogenesis pathways control VSMC function at the postnatal stages including blood pressure and vascular reactivity, we have generated VSMC–specific, tamoxifen-inducible KO (iKO) mice by crossing DGCR8loxp/loxp with SMA-Cre-ERT2 mice[23]. The majority of miRNAs were downregulated and multiple signaling pathways were dysregulated, including two attenuated cellular survival pathways ERK1/2 and AKT in DGCR8iKO mice
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