Harnessing the mechanisms underlying the exacerbated vascular remodelling in Diabetes Mellitus (DM) is pivotal to prevent the high toll of vascular diseases in DM patients. microRNAs (miRNA) regulate vascular smooth muscle cell (VSMC) phenotypic switch. However, miRNA modulation of the detrimental diabetic VSMC phenotype is underexplored. Streptozotocin-induced Type 1 Diabetes (T1DM) Wistar rats and T2DM Zucker rats underwent right carotid artery experimental angioplasty and global miRNA/mRNA expression profiling was obtained by RNA sequencing (RNA-Seq). 2 days after injury a set of 6 miRs were found to be uniquely down-regulated or up-regulated both in VSMCs in T1DM and T2DM. Among these, miR-29c and miR-204 were the most significantly mis-regulated in atherosclerotic plaques from DM patients. miR-29c overexpression and miR-204 inhibition per se attenuated VSMC phenotypic switch in DM. Concomitant miR-29c overexpression and miR-204 inhibition fostered an additive reduction in VSMC proliferation. Epithelial membrane protein 2 (Emp2) and Caveolin-1 (Cav1) mRNAs were identified as direct targets of miR-29c and miR-204, respectively. Importantly, contemporary miR-29c overexpression and miR-204 inhibition in the injured artery robustly reduced arterial stenosis in DM rats. Thus, contemporaneous miR-29c activation and miR-204 inhibition in DM arterial tissues is necessary and sufficient to prevent the exaggerated VSMC growth upon injury.

MicroRNA Regulation of the Hyper-Proliferative Phenotype of Vascular Smooth Muscle Cells in Diabetes Mellitus

TARALLO, Roberta
Investigation
;
GIURATO, Giorgio
Data Curation
;
WEISZ, Alessandro
Supervision
;
2018-01-01

Abstract

Harnessing the mechanisms underlying the exacerbated vascular remodelling in Diabetes Mellitus (DM) is pivotal to prevent the high toll of vascular diseases in DM patients. microRNAs (miRNA) regulate vascular smooth muscle cell (VSMC) phenotypic switch. However, miRNA modulation of the detrimental diabetic VSMC phenotype is underexplored. Streptozotocin-induced Type 1 Diabetes (T1DM) Wistar rats and T2DM Zucker rats underwent right carotid artery experimental angioplasty and global miRNA/mRNA expression profiling was obtained by RNA sequencing (RNA-Seq). 2 days after injury a set of 6 miRs were found to be uniquely down-regulated or up-regulated both in VSMCs in T1DM and T2DM. Among these, miR-29c and miR-204 were the most significantly mis-regulated in atherosclerotic plaques from DM patients. miR-29c overexpression and miR-204 inhibition per se attenuated VSMC phenotypic switch in DM. Concomitant miR-29c overexpression and miR-204 inhibition fostered an additive reduction in VSMC proliferation. Epithelial membrane protein 2 (Emp2) and Caveolin-1 (Cav1) mRNAs were identified as direct targets of miR-29c and miR-204, respectively. Importantly, contemporary miR-29c overexpression and miR-204 inhibition in the injured artery robustly reduced arterial stenosis in DM rats. Thus, contemporaneous miR-29c activation and miR-204 inhibition in DM arterial tissues is necessary and sufficient to prevent the exaggerated VSMC growth upon injury.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4716462
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