The 14q32 microRNA-487b targets the antiapoptotic insulin receptor substrate 1 in hypertension-induced remodeling of the aorta

A Yaël Nossent, Tilde V Eskildsen, Lene B Andersen, Peter Bie, Hasse Brønnum, Mikael Schneider, Ditte C Andersen, Sabine M J Welten, Pia L Jeppesen, Jaap F Hamming, Jakob L Hansen, Paul H Quax, Søren P Sheikh

Publikation: Bidrag til tidsskriftTidsskriftsartikelForskningpeer review

Abstract

OBJECTIVES: To study the role of microRNAs in hypertension-induced vascular pathology before the onset of symptoms of severe cardiovascular disease.

BACKGROUND: MicroRNAs play a crucial role in cardiovascular disease. However, microRNAs are often studied in full-blown cardiovascular disease models, not during development of cardiovascular pathology.

METHODS: Angiotensin II was infused into healthy adult rats, inducing chronic hypertension, and microRNA expression profiles were obtained. The most prominently regulated microRNA, miR-487b, was further investigated, using primary cultures of rat aortic and human umbilical cord arterial cells.

RESULTS: MiR-487b is predicted to target insulin receptor substrate 1 (IRS1). IRS1 plays an important role in both insulin signaling and cell proliferation and survival. IRS1 mRNA and protein levels were downregulated in aortae of hypertensive rats. MiR-487b binds directly to both rat and human IRS1 3'UTR and inhibits reporter gene expression in vitro. In primary rat and human arterial adventitial fibroblasts, inhibition of miR-487b leads to upregulation of IRS1 expression. Upregulation of miR-487b had the opposite effect, confirming direct targeting of IRS1 by miR-487b.Immunohistochemistry of aortic cross sections and rt/qPCR analyses of the separate aortic wall layers showed that both IRS1 and miR-487b were present mainly in the adventitia and less or not at all in the intima and tunica media. IRS1 expression in adventitial fibroblasts was predominantly nuclear and nuclear IRS1 is known to have antiapoptotic effects. Indeed, inhibition of miR-487b protected adventitial fibroblasts, and also medial smooth muscle cells, against serum starvation-induced apoptosis and increased cell survival.

CONCLUSIONS: Angiotensin II-induced hypertension leads to upregulation of miR-487b, which targets IRS1. Via downregulation of IRS1, miR-487b can contribute to cell death and loss of adventitial and medial integrity during hypertension-induced vascular pathology.

OriginalsprogEngelsk
TidsskriftAnnals of Surgery
Vol/bind258
Udgave nummer5
Sider (fra-til)743-753
Antal sider11
ISSN0003-4932
DOI
StatusUdgivet - nov. 2013
Udgivet eksterntJa

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