Nkx2-5 is expressed in atherosclerotic plaques and attenuates development of atherosclerosis in apolipoprotein E-deficient mice

Background--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. methods and results--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. conclusions--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. © 2016 the authors.