Friday, April 26, 2024
4/26/2024
Summary/Abstract Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix (ECM) proteins, especially the elastin breakage, are the determining factors for the development of AAA. Vascular inflammation, particularly macrophage activation and inflammatory SMC phenotype, causes the production of proteolytic enzymes that disrupt ECM homeostasis leading to a weakened vessel wall and consequently AAA formation. However, there is a critical knowledge gap concerning the mechanism(s) or key factor(s) controlling both the vascular inflammation and the ECM dysregulation. Our exciting preliminary data indicate that adenosine deaminase acting on RNA 1 (ADAR1) plays a central role in the induction of inflammatory SMC phenotype, macrophage activation, and AAA formation. ADAR1 deficiency (ADAR1+/-) in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall integrity). ADAR1 knockdown or knockout also inhibits the inflammatory SMC phenotype and macrophage activation. Consequently, ADAR1 knockdown inhibits the expression of inflammation phenotype markers including matrix metalloproteinase-2 and 9 (MMP2/9) in SMCs while restoring contractile SMC markers. In addition, the classical MF activation is blocked when ADAR1 is deleted. Moreover, ADAR1 expression is associated with aneurysm formation in human patients. These data strongly support a novel hypothesis that ADAR1 induces inflammatory SMC phenotype and macrophage activation, leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and human SMCs, in vivo ADAR1 SMC- and macrophage-specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by which ADRA1 promotes MMP2/9 production and activities through its editing and non-editing function; and 2) establish the mechanism by which ADAR1 regulates MF activation; and 3) determine if SMC- or myeloid-specific deletion of ADAR1 attenuates AAA formation. Successful completion of the proposed studies will establish novel mechanisms regulating SMC inflammatory phenotype and vascular inflammation, which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for developing effective therapeutics to treat AAA.
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