Angiotensin II, miR-34a, and AGTRAP crosstalk in arterial smooth muscle cells
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.
Authors
- Sunayana Begum Syed
- Chiara Prampolini
- Maria Cristina Florio (ORCID: https://orcid.org/0000-0002-4524-926X)
- Mirko Baranzini (ORCID: https://orcid.org/0000-0003-0852-010X)
- Angela Raucci (ORCID: https://orcid.org/0000-0003-1333-9671)
- Richard S. Telljohann (ORCID: https://orcid.org/0000-0001-5619-4463)
- Laura Monteonofrio (ORCID: https://orcid.org/0000-0003-3981-942X)
- Robert E. Monticone (ORCID: https://orcid.org/0000-0002-3405-4264)
- Manuel Casaburo (ORCID: https://orcid.org/0000-0002-3395-2708)
- Bruce D. Ziman (ORCID: https://orcid.org/0009-0006-7147-5531)
- Federica Macrì (ORCID: https://orcid.org/0000-0002-9265-4516)
- Alessandra Magenta (ORCID: https://orcid.org/0000-0002-9054-337X)
- Stefania Castiglione (ORCID: https://orcid.org/0000-0002-5999-8368)
- Liqun Jiang (ORCID: https://orcid.org/0000-0002-8541-7539)
- Edward G. Lakatta (ORCID: https://orcid.org/0000-0002-4772-0035)
- Christopher H. Morrell (ORCID: https://orcid.org/0000-0001-5080-7142)
- Julie A. Mattison (ORCID: https://orcid.org/0000-0003-4104-8599)
- M D'agostino (ORCID: https://orcid.org/0000-0002-7682-6357)
- Mingyi Wang (ORCID: https://orcid.org/0000-0001-6412-369X)
- Sara Sileno (ORCID: https://orcid.org/0000-0002-2036-2071)
- Nadia Fanotti
- Maurizio Colognesi-Capogrossi (ORCID: https://orcid.org/0000-0003-1969-5036)
Institutions
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Johns Hopkins Bayview Medical Center (US)
- Centro Cardiologico Monzino (IT)
- Istituto Dermopatico dell'Immacolata (IT)
- Istituto di Farmacologia Traslazionale (IT)
- Institute on Aging (US)
- National Institute on Aging (US)
- National Research Council (IT)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
Publication Details
- Journal
- GeroScience
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1007/s11357-025-02018-5
- Primary Topic
- MicroRNA in disease regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministero della Salute
- National Institutes of Health