Harnessing the mechanisms underlying the exacerbated vascular remodeling in diabetes mellitus (DM) is pivotal to prevent the high toll of vascular diseases in patients with DM. miRNA regulates vascular smooth muscle cell (VSMC) phenotypic switch. However, miRNA modulation of the detrimental diabetic VSMC phenotype is underex-plored. Streptozotocin-induced type 1 DM (T1DM) Wistar rats and type 2 DM (T2DM) Zucker rats underwent right carotid artery experimental angioplasty, and global miRNA/mRNA expression profiling was obtained by RNA sequencing (RNA-Seq). Two days after injury, a set of six miRNAs were found to be uniquely downregulated or upregulated in VSMCs both in T1DM and T2DM. Among these miRNAs, miR-29c and miR-204 were the most significantly misregulated in atherosclerotic plaques from patients with DM. 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.

miRNA Regulation of the Hyperproliferative Phenotype of Vascular Smooth Muscle Cells in Diabetes

Torella D;Indolfi C
2018-01-01

Abstract

Harnessing the mechanisms underlying the exacerbated vascular remodeling in diabetes mellitus (DM) is pivotal to prevent the high toll of vascular diseases in patients with DM. miRNA regulates vascular smooth muscle cell (VSMC) phenotypic switch. However, miRNA modulation of the detrimental diabetic VSMC phenotype is underex-plored. Streptozotocin-induced type 1 DM (T1DM) Wistar rats and type 2 DM (T2DM) Zucker rats underwent right carotid artery experimental angioplasty, and global miRNA/mRNA expression profiling was obtained by RNA sequencing (RNA-Seq). Two days after injury, a set of six miRNAs were found to be uniquely downregulated or upregulated in VSMCs both in T1DM and T2DM. Among these miRNAs, miR-29c and miR-204 were the most significantly misregulated in atherosclerotic plaques from patients with DM. 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.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/378135
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 55
  • ???jsp.display-item.citation.isi??? 55
social impact