The overall goal of this proposal is to establish a novel mechanism by which dedicator of cytokinesis 2 (DOCK2) regulates the phenotypic modulation of vascular smooth muscle cells (SMC). Transition of SMC from a differentiated phenotype to a dedifferentiated state accompanied by neointima formation/vascular remodeling plays a critical role in the development of atherosclerosis, restenosis after angioplasty or bypass, diabetic vascular complications, transplantation arteriopathy, asthma, and cancer. The mechanisms and factors that regulate SMC phenotypic modulation and neointima formation, however, are poorly understood. Under physiological conditions, DOCK2 is only expressed in hematopoietic cells and controls lymphocyte migration and activation by regulating actin cytoskeleton through Rac activation. Our exciting preliminary data demonstrate that platelet derived growth factor (PDGF)-BB, a SMC phenotype modulator, induced DOCK2 expression in SMC. Knockdown of DOCK2 blocked PDGF-BB-induced SMC phenotypic modulation, proliferation, and migration. In vivo animal studies showed that DOCK2 was undetectable in SMC of normal rat carotid arteries, but was induced in the media layer SMC initially and neointimal SMC subsequently following balloon catheter-induced vascular injury. Importantly, knockdown of DOCK2 dramatically inhibited the injury- induced neointima formation. The most conclusive evidence for DOCK2-dependent vascular remodeling/ neointima formation was that knockout of DOCK2 (DOCK2-/-) dramatically blocked artery ligation-induced neointima hyperplasia in mouse carotid artery. Interestingly, DOCK2 is localized in both cell membrane and nuclei of SMC, suggesting that in addition to its role in cytoskeleton/cell migration, DOCK2 may be involved in SMC gene transcription. Indeed, DOCK2 overexpression blocked both SMC gene mRNA expression and myocardin-induced activation of smooth muscle -actin promoter. Thus, the central hypothesis is that DOCK2 regulates SMC phenotypic modulation by suppressing SMC gene transcription and stimulating SMC migration/ proliferation, leading to neointima formation/vascular remodeling. Using primary culture of SMC, in vivo rat balloon injury and mouse wire injury models combining with molecular, cellular and histological approaches, we will 1) study the molecular mechanisms by which DOCK2 modulates SMC phenotype through regulating SMC gene transcription; 2) investigate if DOCK2 induces SMC migration through activation of Rac/RhoA/ Cdc42; and 3) determine the essential role of DOCK2 in SMC phenotypic modulation and vascular remodeling in vivo. The completion of this project will unravel a novel mechanism regulating SMC phenotypic modulation and provide novel insights into whether DOCK2 is a potential therapeutic target for countering vascular damage associated with common diseases including diabetes, restenosis, atherosclerosis, and cancer.
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, transplantation arteriopathy, asthma, and cancer. 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 diseases in vascular and other systems, and most importantly, lead to identification of important novel targets for developing therapeutic agents to treat these diseases.
|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|
|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|
|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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