Saturday, May 21, 2022
5/21/2022
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, ß-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 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 for treatment and prevention of AAA.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
