CX3CL1/CX3CR1 Axis Contributes to Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation and Inflammatory Cyto
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ORIGINAL ARTICLE
CX3CL1/CX3CR1 Axis Contributes to Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation and Inflammatory Cytokine Production Chengsheng Li,1 Jin He,1 Xiaoyi Zhong,1 Hua Gan,1 and Yunfeng Xia1,2
Angiotensin II (Ang II) dysregulation has been determined in many diseases. The CX3CL1/CX3CR1 axis, which has a key role in cardiovascular diseases, is involved in the proliferation and inflammatory cytokine production of vascular smooth muscle cells (VSMCs). In this study, we aim to explore whether Ang II has a role in the expression of CX3CL1/CX3CR1, thus contributing to the proliferation and pro-inflammatory status of VSMCs. Cultured mouse aortic VSMCs were stimulated with 100 nmol/L of Ang II, and the expression of CX3CR1 was assessed by western blot. The results demonstrated that Ang II significantly up-regulated CX3CR1 expression in VSMCs and induced the production of reactive oxygen species (ROS) and the phosphorylation of p38 MAPK. Inhibitors of NADPH oxidase, ROS, and AT1 receptor significantly reduced Ang II-induced CX3CR1 expression. Targeted disruption of CX3CR1 by transfection with siRNA significantly attenuated Ang IIinduced VSMC proliferation as well as down-regulated the expression of proliferating cell nuclear antigen (PCNA). Furthermore, CX3CR1-siRNA suppressed the effect of Ang II on stimulating Akt phosphorylation. Besides, the use of CX3CR1-siRNA decreased inflammatory cytokine production induced by Ang II treatment. Our results indicate that Ang II upregulates CX3CR1 expression in VSMCs via NADPH oxidase/ROS/p38 MAPK pathway and that CX3CL1/CX3CR1 axis contributes to the proliferative and pro-inflammatory effects of Ang II in VSMCs.
Abstract—
KEY WORDS: CX3CR1; Angiotensin II; Vascular smooth muscle cells; Proliferation; Inflammation.
INTRODUCTION Angiotensin II (Ang II) dysregulation has been determined in various chronic diseases, such as nephritis, hypertension, and chronic kidney disease [1]. As the key effector peptide of the renin-angiotensin system, Ang II plays an important role in cardiovascular diseases through 1
Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China 2 To whom correspondence should be addressed at Department of Nephrology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China. E-mail: [email protected]
mechanisms including endothelial dysfunction, vascular remodeling, cell oxidative stress, and pro-inflammatory cytokine secretion in the vascular wall [2]. Ang II exerts multiple effects through initiating downstream signaling molecules, such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK, c-Jun N-terminal kinase, and protein kinase B (Akt) [3]. Prior studies have indicated that Ang II activates signaling response through NADPH oxidase-derived reactive oxygen species (ROS), leading to proliferation and inflammatory responses in vascular smooth muscle cells (VSMCs) [4]. VSMCs are the main component of
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