Angiotensin II, miR-34a, and AGTRAP crosstalk in arterial smooth muscle cells.

Maria Cristina Florio, Sara Sileno, Liqun Jiang, Marco D'Agostino, Sunayana Begum Syed, Laura Monteonofrio, Mirko Baranzini, Chiara Prampolini, Federica Macrì, Manuel Casaburo, Nadia Fanotti, Stefania Castiglione, Robert E Monticone, Bruce Ziman, Richard Telljohann, Mingyi Wang, Julie A Mattison, Christopher H Morrell, Angela Raucci, Edward G Lakatta, Alessandra Magenta, Maurizio Colognesi-Capogrossi

Laboratory of Cardiovascular Science, National Institute On Aging, National Institutes of Health, Baltimore, MD, USA. · pubmed

Paper

Abstract

Arterial aging is associated with enhanced angiotensin II (Ang II) signaling via Ang II type 1 receptor (AT1R) and with microRNA-34a (miR-34a) increased expression. AT1R-associated protein (ATRAP/Agtrap) binds to AT1R, promotes its internalization, and inhibits Ang II signaling. This study addresses the hypothesis that miR-34a targets ATRAP/Agtrap and enhances Ang II pro-inflammatory signaling via AT1R in arterial vascular smooth muscle cells (VSMC). Our results show that miR-34a exhibits an age-associated increase in Rhesus monkey's common carotid artery and rat aorta. Further, AGTRAP protein expression is lower in old rat VSMC and in old mice aorta. Ang II enhances miR-34a in old rat VSMC and human aortic smooth muscle cells (HASMC), and inhibits AGTRAP and sirtuin 1 (SIRT1) mRNA/protein expression. In miR-34a-overexpressing HASMC, AGTRAP and SIRT1 mRNA/protein decrease, and these effects are rescued by AGTRAP forced expression. Moreover, miR-34a directly targets AGTRAP and AGTRAP downmodulation further enhances miR-34a expression decreasing SIRT1 in HASMC. Finally, Ang II and miR-34a induce the upregulation of pro-inflammatory genes, interleukin (IL)-6, cyclooxygenase 2 (COX2), monocyte chemoattractant protein-1 (MCP-1), and milk fat globule-epidermal growth factor 8 (MFGE8) in HASMC, and this effect is abolished by AGTRAP forced expression. In conclusion, Ang II upregulates miR-34a, activating a negative feedback loop on AGTRAP that reinforces Ang II signaling. The age-associated AGTRAP downmodulation in central arteries and VSMC underlies a potential miR-34a/AGTRAP role in vascular aging.

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Research summary

The paper claims that miR-34a enhances Ang II pro-inflammatory signaling by targeting AGTRAP, which is implicated in vascular aging. This research addresses mechanisms underlying arterial aging, contributing to the understanding of age-related vascular changes.

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