title: Significance of the transcription factor KLF5 in cardiovascular remodeling.
abstract: Structural remodeling of the heart and blood vessels is an important pathologic process in the development of many cardiovascular diseases. However, transcriptional regulation of altered gene expression during cardiovascular remodeling is not well understood. We previously isolated KLF5/basic transcription element-binding (BTEB)2, a Krüppel-like factor, as a transcription factor that binds the promoter of the embryonic smooth muscle myosin heavy chain gene (SMemb). KLF5 activates many genes inducible during cardiovascular remodeling, such as platelet-derived growth factor (PDGF)-A/B, Egr-1, plasminogen activator inhibitor-1 (PAI-1), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) receptors. KLF5 is abundantly expressed in embryonic smooth muscles and is down-regulated with vascular development, but reinduced in proliferative neointimal smooth muscles in response to vascular injury. In KLF5 gene-targeted mice, homozygotes die at an early embryonic stage whereas heterozygotes are apparently normal. However, in response to external stress, arteries of heterozygotes exhibit diminished levels of smooth muscle and adventitial cell activation. Furthermore, angiotensin II-induced cardiac hypertrophy and fibrosis are attenuated in heterozygotes. KLF5 activities are regulated by many transcriptional regulators and nuclear receptors, such as retinoic acid receptor-alpha (RAR alpha), NF-kappaB, PPAR gamma, p300, and SET. Interestingly, RAR alpha agonist suppresses KLF5 and cardiovascular remodeling, whereas RAR alpha antagonist activates KLF5 and induces angiogenesis. These results indicate that KLF5 is an essential transcription factor in cardiovascular remodeling and a potential therapeutic target for cardiovascular disease.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. nagai-tky@umin.ac.jp
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Aizawa
authors.forename: T
authors.initials: T
authors.lastname: Shindo
authors.forename: I
authors.initials: I
authors.lastname: Manabe
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism*; D003433:Crosses, Genetic; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D006720:Homozygote; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010802:Phylogeny; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C075278:platelet-derived growth factor A; D000804:Angiotensin II