Abstract
Background: Renin-Angiotensin Aldosterone System (RAAS) activation plays a central role in vascular aging, leading to structural and functional alterations including vascular smooth muscle cell (VSMC) proliferation, migration and secretion of extracellular matrix and inflammatory molecules. The age-associated increase in Angiotensin II (Ang II) expression enhances AT1-receptor activity and determinates a pro-fibrotic and pro-inflammatory phenotype. Further, miR-34a expression is modulated by aging and increases in different tissues, including the mouse aorta, but no direct miR-34a target has been identified in the RAAS pathway that sustains age-dependent increase of pro-inflammatory signaling. Aims: The aim of our study is to evaluate the potential interaction between miR-34a and RAAS signaling in VSMCs. Methods and Results: miR-34a expression exhibited an age-dependent increase in Rhesus Monkey (8- to 26-year-old) and rat central arteries (8- and 30-month-old). In silico analysis indicated that AT1R-associated protein (AGTRAP), a negative modulator of AT1R signaling, is a potential miR-34a target suggesting that the age-dependent increase in miR-34a in the arterial vascular wall may decrease AGTRAP expression in arterial VSMC. Ang II enhanced miR-34a expression in 30-month-old rat and in human aorta SMCs (HASMCs), whereas AGTRAP and Sirtuin-1 (SIRT1) mRNA and protein level decreased. Immunohistochemistry analysis showed a decrease of AGTRAP in 18-month-old miR-34a knock-out mice compared to 2-month-old mice. By luciferase assay, we demonstrated that AGTRAP is a direct miR-34a target. Moreover, AGTRAP and SIRT1 decreased in HASMCs infected with miR-34a-encoding lentivirus and this effect was partially rescued in AGTRAP/miR-34a co-infected cells. Finally, pro-inflammatory genes IL-6, COX-2, MCP-1 and MFG-E8 expression was upregulated in Ang II-treated and miR-34a overexpressing HASMCs, and this effect was abolished in AGTRAP/miR-34a co-transfected cells. Conclusions: Our results show cross-modulation between miR-34a and AGTRAP. MiR-34a targeting AGTRAP increases the expression of pro-inflammatory molecules in VSMCs and represents a novel mechanism that modulates RAAS signaling in vascular aging. Statement: This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.
Published Version
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