Year: 2025
Type: article
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.
Source: GeroScience
Authors: 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
Institutions: National Institutes of Health, National Institute on Aging, Istituto Dermopatico dell'Immacolata, Instituto Nazionale Tumori Regina Elena, Centro Cardiologico Monzino, Istituto di Farmacologia Traslazionale, National Research Council, Johns Hopkins University, Johns Hopkins Bayview Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,890
Award: G249627624
OpenAlex ID: W4416670943