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 M? 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 M? 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.

Public Health Relevance

Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix proteins, especially the elastic lamellae of the media, are the determining factors for the development of AAA. In this application, a combination of molecular, cellular, and genetic approaches with gain-of- and loss-of-function studies will be used to establish novel mechanisms by which adenosine deaminase acting on RNA 1 promotes AAA formation by mediating matrix metalloproteinase (MMP2/9) production and macrophage activation. The outcome of the project may lead to the development of new strategies for the prevention and therapy of AAA.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL119053-05
Application #
9885780
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Mcdonald, Cheryl
Project Start
2014-02-01
Project End
2024-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
DUNS #
City
Columbia
State
MO
Country
United States
Zip Code
65211
Chen, Sisi; Mei, Xiaohan; Yin, Amelia et al. (2018) Response gene to complement 32 suppresses adipose tissue thermogenic genes through inhibiting ?3-adrenergic receptor/mTORC1 signaling. FASEB J 32:4836-4847
Wang, Yung-Chun; Chuang, Ya-Hui; Shao, Qiang et al. (2018) Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice. J Biol Chem 293:5668-5678
Dong, Kun; Guo, Xia; Chen, Weiping et al. (2018) Mesenchyme homeobox 1 mediates transforming growth factor-? (TGF-?)-induced smooth muscle cell differentiation from mouse mesenchymal progenitors. J Biol Chem 293:8712-8719
Shi, Ning; Chen, Shi-You (2018) Smooth Muscle Cells Move With Mitochondria. Arterioscler Thromb Vasc Biol 38:1255-1257
Sun, Chenming; Chen, Shi-You (2018) RGC32 Promotes Bleomycin-Induced Systemic Sclerosis in a Murine Disease Model by Modulating Classically Activated Macrophage Function. J Immunol 200:2777-2785
Cui, Xiao-Bing; Luan, Jun-Na; Dong, Kun et al. (2018) RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis. Arterioscler Thromb Vasc Biol 38:e36-e47
Cui, Xiao-Bing; Luan, Jun-Na; Dong, Kun et al. (2018) Response by Cui et al to Letter Regarding Article, ""RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis"". Arterioscler Thromb Vasc Biol 38:e97-e98
Tang, Jun-Ming; Shi, Ning; Dong, Kun et al. (2018) Response Gene to Complement 32 Maintains Blood Pressure Homeostasis by Regulating ?-Adrenergic Receptor Expression. Circ Res 123:1080-1090
Cui, Xiao-Bing; Chen, Shi-You (2018) Response Gene to Complement 32 in Vascular Diseases. Front Cardiovasc Med 5:128
Guo, Xia; Li, Feifei; Xu, Zaiyan et al. (2017) DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure. J Lipid Res 58:1777-1784

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