KLF5/BTEB2, a Krüppel-like zinc-finger type transcription factor, mediates smooth muscle cell activation as well as cardiovascular remodeling

Phenotypic modulation of smooth muscle from the contractile to the synthetic type underlies the pathogenesis of atherosclerosis. We previously isolated a transcription factor, KLF5 (also known as BTEB2 and IKLF), to activate various gene promoters that are activated in phenotypically modulated smooth muscle cells, such as embryonic smooth muscle myosin heavy chain gene (SMemb), plasminogen activator inhibitor-1 (PAI-1), iNOS, PDGF-A, Egr-1 and VEGF receptors. KLF5 is downregulated with vascular development but upregulated in neointima. Chromatin immunoprecipitation assay showed KLF5 to be induced and to bind the promoter of the PDGF-A gene in response to angiotensin II stimulation. To define the role of KLF5 in cardiovascular remodeling, we targeted the KLF5 gene in mice. In response to external stress, arteries of heterozygotes exhibited diminished levels of smooth muscle and adventitial cell activation. We also found that RARα binds KLF5, and that Am80, a potent synthetic RAR agonist, inhibits angiotensin II-induced cardiac hypertrophy. These results indicate that KLF5 is an essential transcription factor that causes not only smooth muscle phenotypic modulation but also cardiac hypertrophy and fibrosis.