# Role of miR-146a in Abdominal Aortic Aneurysm > **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $494,578 ## Abstract Abstract Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta with a high mortality greater than 80% after rupture. Aortic vascular smooth muscle cells (SMCs) are pivotal in maintaining aortic structural integrity and function, and SMC-rich aortic medial stability is highly disrupted in AAA. Currently, besides surgical interventions, no alternative therapeutics are available to blunt AAA progression and rupture. Consequently, there is a dire need to identify novel strategies for development of effective, non-surgical therapeutics. MicroRNA-146a (miR-146a), a well-known regulator of inflammation and auto-immunity, is highly expressed in aneurysmal tissue of AAA patients. However, the role of miR-146a in SMC homeostasis and AAA remains to be explored. In preliminary studies, by in-situ hybridization, we observed that miR-146a is upregulated in SMC-rich aortic media of human and mouse AAAs; miR-146a deficiency significantly promoted Angiotensin II (AngII) -induced AAA formation in normolipidemic mice co-administered with Lysyl oxidase inhibitor, β-aminopropionitrile (BAPN); and mimetics-mediated miR-146a overexpression abolished AngII-induced AAAs in both hypercholesterolemic LDLr-/- mice and normolipidemic mice co-infused with BAPN. To elucidate underlying mechanisms, by RNA sequencing, we identified novel targets from miR-146a deficiency experiments: TFIID-31, a TATA binding protein associated factor involved in transcriptional activation and repression, is significantly upregulated; whereas Beclin-1, a gene indispensable for autophagy induction and USP9X, a deubiquitinase critical for Beclin-1 stabilization, are significantly downregulated. Autophagy, a self-regulatory process by which cells digest, and recycle their cytoplasmic materials for energy purposes under stress. Our preliminary study also showed an increased Beclin-1 in mouse AAAs, as observed in human AAAs and Tat-peptide mediated Beclin-1 activation suppressed AngII-induced AAA formation in mice. In addition, miR-146a overexpression significantly suppressed TFIID-31, promoted USP9X and Beclin-1, and ShRNA-mediated silencing of TFIID-31 increased USP9X in cultured aortic SMCs. Based on these observations, we will test our central hypothesis that miR-146a activation protects against AAA formation and progression by promoting Beclin-1-mediated aortic SMC homeostasis. By utilizing our unique mice models generated specifically for these studies, we propose 3 aims. Aim 1 will test our working sub-hypothesis that miR-146a promotes Beclin-1 stability in aortic SMCs via a TFIID-31-USP9X –dependent manner. Aim 2 will test our working sub-hypothesis that miR-146a activation protects against AAA through activation of SMC-Beclin-1-derived autophagy. Aim 3 will determine the effect of miR-146a / Beclin-1 activation on progression of established AAAs. In summary, we will delineate the protective role of Beclin-1 in AAA and establish miR-146a activation as a novel therapeut... ## Key facts - **NIH application ID:** 10745356 - **Project number:** 5R01HL156957-03 - **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA - **Principal Investigator:** Venkateswaran Subramanian - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $494,578 - **Award type:** 5 - **Project period:** 2022-01-01 → 2025-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10745356 ## Citation > US National Institutes of Health, RePORTER application 10745356, Role of miR-146a in Abdominal Aortic Aneurysm (5R01HL156957-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10745356. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*