ADAR1 in abdominal aortic aneurysm

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 MΦ 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 MΦ 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.

Grant Number: 5R01HL119053-08
NIH Institute/Center: NIH
Principal Investigator: Shiyou Chen