Premium
Significance of the transcription factor KLF5 in cardiovascular remodeling
Author(s) -
NAGAI R.,
SUZUKI T.,
AIZAWA K.,
SHINDO T.,
MANABE I.
Publication year - 2005
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2005.01366.x
Subject(s) - biology , transcription factor , fibrosis , angiogenesis , endocrinology , vascular smooth muscle , vascular remodelling in the embryo , medicine , cancer research , microbiology and biotechnology , gene , biochemistry , smooth muscle
Summary. 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‐ α (RAR α ), NF‐ κ B, PPAR γ , p300, and SET. Interestingly, RAR α agonist suppresses KLF5 and cardiovascular remodeling, whereas RAR α 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.