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Biochim Biophys Acta. 2014 Feb;1842(2):275-83. doi: 10.1016/j.bbadis.2013.12.001. Epub 2013 Dec 9.

Adipocyte-derived factors impair insulin signaling in differentiated human vascular smooth muscle cells via the upregulation of miR-143.

Author information

1
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany.
2
Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center, Duesseldorf, Germany.
3
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
4
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Duesseldorf, Germany; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. Electronic address: margriet.ouwens@ddz.uni-duesseldorf.de.

Abstract

Cardiovascular complications are common in patients with type 2 diabetes. Adipokines have been implicated in the induction of proliferative and pro-atherogenic alterations in human vascular smooth muscle cells (hVSMC). Other reports demonstrated the importance of the miRNA cluster miR-143/145 in the regulation of VSMC homeostasis and insulin sensitivity. Here we investigated whether the detrimental effects of adipokines on hVSMC function could be ascribed to alterations in miR-143/145 expression. The exposure of hVSMC to conditioned media (CM) from primary human subcutaneous adipocytes increased the expression of smooth muscle α-actin (SMA), and the miR-143/145 cluster, but markedly impaired the insulin-mediated phosphorylation of Akt and its substrate endothelial nitric oxide synthase (eNOS). Furthermore, CM promoted the phosphorylation of SMAD2 and p38, which have both been linked to miR-143/145 induction. Accordingly, the induction of miR-143/145 as well as the inhibition of insulin-mediated Akt- and eNOS-phosphorylation was prevented when hVSMC were treated with pharmacological inhibitors for Alk-4/5/7 and p38 before the addition of CM. The transfection of hVSMC with precursor miR-143, but not with precursor miR-145, resulted in impaired insulin-mediated phosphorylation of Akt and eNOS. This inhibition of insulin signaling by CM and miR-143 is associated with a reduction in the expression of the oxysterol-binding protein-related protein 8 (ORP8). Finally, the knock-down of ORP8 resulted in impaired insulin-mediated phosphorylation of Akt in hVSMC. Thus, the detrimental effects of adipocyte-derived conditioned media on insulin action in primary hVSMC can be ascribed to the Alk- and p38-dependent induction of miR-143 and subsequent downregulation of ORP8.

KEYWORDS:

Adipokines; Insulin signaling; Vascular smooth muscle cells; miRNA; p38

PMID:
24333576
DOI:
10.1016/j.bbadis.2013.12.001
[Indexed for MEDLINE]
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