title: Nkx2-5 Is Expressed in Atherosclerotic Plaques and Attenuates Development of Atherosclerosis in Apolipoprotein E-Deficient Mice.
abstract: NK2 homeobox 5 (Nkx2-5) is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages. Embryos lacking Nkx2-5 are nonviable attributed to growth retardation and gross abnormalities of the heart. However, the role of Nkx2-5 in atherosclerosis remains elusive. This study aims to elucidate the specific functions of Nkx2-5 during atherogenesis and in established atherosclerotic plaques.
  
  
  
  Two types of atherosclerotic lesions were created in ApoE-/-mice through 2 different dietary manipulations. Mice fed a standard chow diet were sacrificed at 20 weeks old, a time point at which mice developed early-stage atherosclerotic lesions. The other half of mice were fed a western diet from 6 to 22 weeks old and then sacrificed. These mice demonstrated advanced atherosclerosis. No Nkx2-5 was detected in normal arteries; however, it was abundantly present in the intima of atherosclerotic lesions and localized in macrophages and smooth muscle cells. Adenovirus gene transfer of Nkx2-5 markedly ameliorated and stabilized the atherosclerotic plaques, and knockdown of Nkx2-5 significantly exacerbated the disease. Molecular studies indicated that expression of specific members of matrix metalloproteinases and tissue inhibitor of metalloproteinases, which play a crucial role in the progression of atherosclerosis, were directly regulated by Nkx2-5. Furthermore, we demonstrated that the compromised endothelial function, which was considered as a hallmark of early atherosclerosis, could be improved by Nkx2-5 gene transfer.
  
  
  
  Nkx2-5 exerts antiatherogenic effects, which may partly be attributed to regulation on matrix metalloproteinases and tissue inhibitor of metalloproteinases, thus stabilizing atherosclerotic plaque; besides, it improves endothelial function by inhibiting leukocyte adhesion to the endothelium.
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Du
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiangrao
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China unionhuang@163.com.|Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004036:Diet, Atherogenic; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D000072576:Homeobox Protein Nkx-2.5 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000209:etiology* / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D000072576:Homeobox Protein Nkx-2.5; C484469:Nkx2-5 protein, mouse; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
keywords: NK2 homeobox 5; atherosclerosis; matrix metalloproteinases; plaque stability