Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury.
Bach1 is a transcriptional repressor of the cytoprotective enzyme heme oxygenase-1 (HO-1). Although HO-1 protects against atherosclerosis, the function of Bach1 in this process is poorly understood. We isolated peritoneal macrophages and aortic smooth muscle cells (SMC) from wild-type and bach1-deficient mice. bach1-Deficient macrophages expressed increased levels of HO-1 and showed elevated phagocytic activity when incubated with 0.75 microm microspheres. In SMC, bach1-ablation resulted in increased expression of HO-1 and decreased proliferation in bromodeoxyuridine incorporation assay as compared with wild-type cells. The up-regulated phagocytic activity and reduced SMC proliferation of bach1-deficient cells were not restored by Zinc (II) protoporphyrin IX, an inhibitor of HO, suggesting that HO-independent mechanisms are also involved in the regulation of phagocytosis of macrophages and proliferation of SMC by Bach1. In wild-type mice, cuff placement around femoral artery caused pronounced intimal proliferation without affecting the media, thus resulting in intimal to medial (I/M) volume ratio of 65.6%. bach1-deficient mice had less degree of intimal growth (I/M ratio of 45.6%). These results indicate that Bach1 plays a critical role in the regulation of HO-1 expression, macrophage function, SMC proliferation and neointimal formation. Bach1 may regulate gene expression in these cells during inflammation and atherogenesis.
Omura
Shinji
S
Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8551, Japan.
Suzuki
Hiroshi
H
Toyofuku
Mamoru
M
Ozono
Ryoji
R
Kohno
Nobuoki
N
Igarashi
Kazuhiko
K
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008565:Membrane Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse