Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation

Yanan Zou, Zixuan Chen, Brett L. Jennings, Guannan Zhao, Qingqing Gu, Anindya Bhattacharya, Yan Cui, Bo Yu, Kafait Malik, Junming Yue

Research output: Contribution to journalArticle

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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 DGCR8 loxp/loxp with VSMC specific tamoxifen-inducible Cre transgenic mice SMA-Cre-ER T2 . 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.

Original languageEnglish (US)
Article number19660
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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DiGeorge Syndrome
Neointima
Vascular Smooth Muscle
Smooth Muscle Myocytes
Blood Vessels
MicroRNAs
Blood Pressure
Tamoxifen
Down-Regulation
RNA-Binding Proteins
MAP Kinase Signaling System
Differentiation Antigens
Cell Nucleus
Knockout Mice
Transgenic Mice
Cell Movement
Cell Differentiation
Body Weight
Cell Proliferation
Enzymes

All Science Journal Classification (ASJC) codes

  • General

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Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation. / Zou, Yanan; Chen, Zixuan; Jennings, Brett L.; Zhao, Guannan; Gu, Qingqing; Bhattacharya, Anindya; Cui, Yan; Yu, Bo; Malik, Kafait; Yue, Junming.

In: Scientific Reports, Vol. 8, No. 1, 19660, 01.12.2018.

Research output: Contribution to journalArticle

Zou, Yanan ; Chen, Zixuan ; Jennings, Brett L. ; Zhao, Guannan ; Gu, Qingqing ; Bhattacharya, Anindya ; Cui, Yan ; Yu, Bo ; Malik, Kafait ; Yue, Junming. / Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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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 DGCR8 loxp/loxp with VSMC specific tamoxifen-inducible Cre transgenic mice SMA-Cre-ER T2 . 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.",
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AU - Gu, Qingqing

AU - Bhattacharya, Anindya

AU - Cui, Yan

AU - Yu, Bo

AU - Malik, Kafait

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