Date Available

2-10-2023

Year of Publication

2023

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

First Advisor

Dr. Venkateswaran Subramanian

Abstract

Abdominal Aortic Aneurysms (AAAs) are permanent dilations of the abdominal aorta with greater than 80% mortality after rupture. Currently, there are no proven non-surgical therapeutics to blunt expansion or rupture, which highlights the need to gain mechanistic insights into AAA formation. AAA formation involves a complex process of destruction of aortic media through activation of matrix metalloproteinases (MMPs), loss of smooth muscle cells, degradation of extracellular matrix proteins like elastin and collagen, and inflammation. Autophagy is a well-conserved cellular process whereby damaged cytoplasmic organelles and long-lived proteins are degraded. Cellular autophagic activity is usually low under normal conditions but can be markedly dysregulated in pathophysiological conditions. Recent human AAA tissue characterization studies showed an accelerated autophagy process in AAAs. However, the functional association of enhanced autophagy in AAA formation and development is unclear. In this study, utilizing the well-established AngII-induced AAA mouse model, we identified that, similar to human studies, autophagy proteins like Beclin-1 and LC3-II are increased in the abdominal aorta of the AngII-infused hypercholesterolemic male mice. Then, we utilized both pharmacological and genetic approaches to further elucidate the contribution of autophagy in aortic aneurysms. Administration of 3-methyl adenine (3-MA), an autophagy inhibitor did not influence AngII-induced AAA formation. On the other hand, Celastrol, an autophagy inducer compound failed to influence autophagy proteins in our AngII-induced AAA mouse model. However, for the first time, we demonstrated that Celastrol supplementation, independent of autophagy activation, promoted AngII-induced AAA formation and ablate sexual dimorphism in male and female mice. Accelerated AngII-induced AAA development by Celastrol supplementation was associated with increased MMP activation and aortic medial destruction. To further investigate the role of autophagy in aortic aneurysm formation, we generated tamoxifen-inducible smooth muscle cell-specific Beclin-1, a key protein involved in autophagy induction, deficient mice either in normolipidemic or hypercholesterolemic (LDL receptor-deficient) backgrounds. Using this unique mouse model, we demonstrated that, Beclin-1 deficiency in SMCs accelerated ascending and abdominal aortic expansion independent of AngII. Beclin-1 deficiency exacerbated aortic medial elastin fiber destruction, loss of medial SMCs, and collagen deposition in the adventitial layer. In summary, our findings suggested that Beclin-1, an essential autophagic protein, plays a critical role in the maintenance of aortic structural integrity during AAA formation and development.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2023.032

Funding Information

This work is supported by R01 grants from NIHNHLBI R01HL-130086 and R01HL-156957.

Download

Share

COinS