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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, for which only 10% of patients are eligible, 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 remain 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) and Lysyl oxidase inhibitor, β-aminopropionitrile (BAPN)-induced AAA formation in normolipidemic mice; and mimetics-mediated miR-146a overexpression abolished AngII+BAPN-induced AAAs in mice. 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. Increased autophagy has been observed in human AAAs. Our preliminary study also showed an increased autophagy in mouse AAAs. In addition, in cultured aortic SMCs, overexpression of miR-146a significantly suppressed TFIID-31, promoted USP9X and Beclin-1, and ShRNA-mediated silencing of TFIID-31 increased USP9X. 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 animal 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: Determine the effect of miR-146a / Beclin-1 activation on progression of established AAAs. In summary, we will characterize the protective role of Beclin-1 in AAA and establish miR-146a activation as a novel therapeutic strategy against AAA by targeting SMC-Beclin-1. This mechanistic research will set solid preclinical evidence that targeting miR-146a represents a novel therapeutic strategy and may lead to a breakthrough for treatment and prevention of AAA.
|Effective start/end date||1/1/22 → 8/31/22|
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