Vascular smooth muscle (SMC) phenotypic modulation, the transition from a contractile to a proliferative phenotype accompanied by neointima formation following vascular injury, plays a critical role in the development and progression of several proliferative cardiovascular diseases such as atherosclerosis, hypertension, restenosis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. The regulatory mechanisms underlying SMC phenotypic modulation, however, are poorly understood. A hallmark feature of the phenotypic modulation is the down-regulation of SMC contractile genes. Platelet-derived growth factor-BB (PDGF-BB), a well-known stimulator of SMC phenotypic modulation, down- regulates SMC gene expression and stimulates SMC proliferation via posttranscriptional regulation of the related genes. The post-transcriptional mechanisms involved in SMC phenotype gene expression, however, remain largely unknown. Our exciting preliminary data indicate that the down-regulation of SMC contractile genes is caused by abnormal RNA editing of their precursor mRNAs (pre-mRNAs). This abnormal pre-mRNA editing is facilitated by adenosine deaminase acting on RNA (ADAR), which converts adenosines to inosines (A->I editing). A-to-I RNA editing of the pre-mRNA transcripts from introns or 3'-untranslated regions alters pre- mRNA splicing, leading to decreased mature mRNA levels and abnormal cellular functions. PDGF-BB induces ADAR1 while down-regulating SMC myosin heavy chain (SMMHC) and calponin (CNN). Knockdown of ADAR1 by shRNA restores PDGF-BB-blocked SMMHC and CNN expression, demonstrating that ADAR1 plays an essential role in SMC phenotype modulation. ADAR1 appears to be also important for PDGF-BB-induced SMC proliferation/survival. In vivo studies show that SMMHC and CNN pre-mRNA is accumulated when their mature mRNA is decreased in balloon-injured rat carotid arteries. Moreover, ADAR1 is highly induced in media layer SMCs initially, and neointima SMCs subsequently following the injury. Of importance, knockdown of ADAR1 dramatically inhibits injury-induced neointima formation, demonstrating a critical role of ADAR1 in vascular remodeling in vivo. These seminal findings strongly support a novel hypothesis that ADAR1/abnormal RNA editing mediates PDGF-BB-induced down-regulation of SMC contractile genes and SMC proliferation/survival, leading to SMC phenotypic modulation and vascular remodeling. Using primary culture of SMCs, in vivo rat balloon injury and mouse wire injury models combining with molecular, cellular and histological approaches, we will 1) determine the role and mechanism whereby ADAR1 modulates SMC phenotype; 2) elucidate the molecular mechanisms underlying ADAR1 function in regulating SMC proliferation/survival; and 3) study the role of ADAR1 in SMC phenotypic modulation and vascular remodeling in vivo. Successful completion of these aims will unravel a novel mechanism governing SMC phenotypic modulation, which will ultimately lead to identification of novel targets for developing therapeuti agents to treat proliferative vascular diseases.

Public Health Relevance

Cardiovascular disease is the #1 cause of mortality in the United States. Transition of vascular smooth muscle (SMC) from a differentiated phenotype to a proliferative state accompanied by neointima formation plays a critical role in the development of atherosclerosis, hypertension, restenosis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. In this application, a combination of molecular, cellular, and genetic approaches with gain-of-function and loss-of-function studies will be used to establish a novel mechanism underlying SMC phenotypic modulation. The completion of this project will advance our understanding of the fundamental pathologic mechanisms that contribute to the progression of aforementioned proliferative vascular diseases, and most importantly, lead to identification of important novel targets for developing therapeutic agents to treat these diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Olive, Michelle
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Georgia
Schools of Veterinary Medicine
United States
Zip Code
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
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
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

Showing the most recent 10 out of 35 publications