title: siRNA-mediated silencing of Wnt5a regulates inflammatory responses in atherosclerosis through the MAPK/NF-κB pathways.
abstract: Previous studies have demonstrated that the aberrant expression of Wnt5a occurs in atherosclerotic lesions. However, the precise role of Wnt5a in the pathogenesis of atherosclerosis remains largely unknown. The present study was undertaken to determine whether the RNA interference of Wnt5a in vivo by adenovirus (Ad)-mediated small interfering RNA (siRNA) transfection is capable of inhibiting the progression of atherosclerosis. Recombinant adenovirus carrying siRNA targeting Wnt5a (Ad-Wnt5a siRNA) was designed. Male apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-fat diet to induce the pathogenesis of atherosclerosis. Mice were randomly divided into 3 groups (n=15 in each group): the mock group, which received treatment with phosphate-buffered saline (PBS); the Ad-NC group, which received treatment with Ad-non-specific siRNA; and the Ad-Wnt5a siRNA group, which received treatment with Ad-Wnt5a siRNA. Treatment with Ad-Wnt5a siRNA markedly inhibited the mRNA and protein expression of Wnt5a in the aortic tissues. The knockdown of Wnt5a had no significant effect on blood lipid levels, but it suppressed atherosclerotic development and increased plaque stability, which was determined by hematoxylin and eosin staining, picrosirius red staining and Oil Red O staining. Furthermore, the mRNA and protein expression of inflammatory cytokines, including monocyte chemotactic protein-1 (MCP-1), cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-2 and MMP-9 was significantly downregulated in the Ad-Wnt5a siRNA group. In addition, the knockdown of Wnt5a inhibited the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. These results demonstrate that Ad-mediated Wnt5a silencing in vivo attenuates the development of atherosclerotic disease by reducing inflammatory mediators involved in the MAPK/NF-κB pathways.
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Lei
authors: L
authors: Yang
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Yingjie
authors: Y
authors: Chu
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Yuhang
authors: Y
authors: Wang
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Xiangmei
authors: X
authors: Zhao
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Wenke
authors: W
authors: Xu
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Peirong
authors: P
authors: Zhang
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Xiaoyu
authors: X
authors: Liu
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Shujuan
authors: S
authors: Dong
authors: Department of Emergency Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Wenqi
authors: W
authors: He
authors: Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China.
authors: Chuanyu
authors: C
authors: Gao
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D008055:Lipids; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020928:Mitogen-Activated Protein Kinases