Adenosine deaminase acting on RNA (ADAR1) in the development of abdominal aortic aneurysm and atherosclerosis
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The main focus of this dissertation is the role of Adenosine deaminase acting on RNA (ADAR1) in the development of abdominal aortic aneurysm (AAA) and atherosclerosis. This first chapter of this document presents a review of the literature, while the second chapter focuses on experimental studies defining the contribution of ADAR1 to the progression of abdominal aortic aneurysm. The principal outcome of this study includes: 1) ADAR1 expression is induced in abdominal aortic smooth muscle cell in both mouse and human AAA tissues. 2) Heterozygous knockout of ADAR1 diminishes the Ang II-induced AAA/dissection in ApoE-/- mice. 3) Mouse aortic transplantation indicates that ADAR1 in vascular cells is essential for AAA formation. 4) SMC-specific ADAR1 deficiency reduces experimental AAA formation/dissection. 5) Mechanistically, ADAR1 physically interacts with human antigen R (HuR) to increase the stability of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) mRNA, leading to increased MMP levels and activities. Thus, ADAR1 is a novel regulator of AAA development/dissection, and thus may represent a potentially new therapeutic target to prevent AAA growth and rupture. The third chapter focuses on defining the role of ADAR1 in the development of atherosclerosis and plague stability. In these studies, ADAR1 protein expression is found to be significantly induced in vascular SMCs in human and mouse atherosclerotic plaque and mediate MMP2 expression via the phosphoinositide 3-kinase (PI3K)-Akt pathway. ADAR1 further promotes flexible transcription of MMP2 via disinhibiting Z-DNA. Our data suggest that endogenous ADAR1 is an important and previously unrecognized regulator of VSMC MMP expression and atherosclerosis. Thus, ADAR1 represents a novel and promising drug target for potential treatment of atherosclerosis. In summary, our studies highlight the significance of ADAR1 in exacerbating the formation of both abdominal aortic aneurysm and atherosclerosis. Ongoing and future studies are aimed at exploring therapeutic methods by targeting ADAR1.
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Ph. D.