Krüppel-like Factors KLF2, KLF4, and KLF5: Central Regulators of Smooth Muscle Function
The vascular smooth muscle cell (SMC) plays a vital role in mammalian physiology through its regulation of blood pressure via contraction and relaxation. In response to vascular injury, it is capable of rapidly and reversibly modulating its pheno-type to a cell type capable of performing a number of functions key to wound healing and vascular inflammation including migration, proliferation, matrix synthesis, chem-okine production, and protein synthesis. Recent work has identified three Krüppel-like factors—KLF2, KLF4, KLF5—as intricately involved in all of these processes. This review provides a brief overview of the role these factors play in regulating these and other key SMC functions.
KeywordsSerum Response Factor Neointima Formation Phenotypic Switching KLF4 Expression Smooth Muscle Cell Growth
Unable to display preview. Download preview PDF.
- Adam PJ, Regan CP, Hautmann MB, and Owens GK (2000) Positive- and negative-acting Kruppel-like transcription factors bind a transforming growth factor β control element required for expression of the smooth muscle cell differentiation marker SM22α in vivo. J. Biol Chem. 275:37798–37806PubMedCrossRefGoogle Scholar
- Hoshino Y, Kurabayashi M, Kanda T, Hasegawa A, Sakamoto H, Okamoto Ei, Kowase K, Watanabe N, Manabe I, Suzuki T, Nakano A, Takase Si, Wilcox JN, and Nagai R (2000) Regulated expression of the BTEB2 transcription factor in vascular smooth muscle cells: Analysis of developmental and pathological expression profiles shows implications as a predictive factor for restenosis. Circulation 102:2528–2534PubMedGoogle Scholar
- Knipp BS, Ailawadi G, Ford JW, Peterson DA, Eagleton MJ, Roelofs KJ, Hannawa KK, Deogracias MP, Ji B, Logsdon C, Graziano KD, Simeone DM, Thompson RW, Henke PK, Stanley JC, and Upchurch GR, Jr. (2004) Increased MMP-9 expression and activity by aortic smooth muscle cells after nitric oxide synthase inhibition is associated with increased nuclear factor-kappaB and activator protein-1 activity. J. Surg. Res. 116:70–80PubMedCrossRefGoogle Scholar
- Kozaki K, Kaminski WE, Tang J, Hollenbach S, Lindahl P, Sullivan C, Yu JC, Abe K, Martin PJ, Ross R, Betsholtz C, Giese NA, and Raines EW (2002) Blockade of Platelet-Derived Growth Factor or Its Receptors Transiently Delays but Does Not Prevent Fibrous Cap Formation in ApoE Null Mice. Am J Pathol 161:1395–1407PubMedGoogle Scholar
- Marumo T, Schini-Kerth VB, Fisslthaler B, and Busse R (1997) Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-κB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells. Circulation 96:2361–2367PubMedGoogle Scholar
- Miyamoto S, Suzuki T, Muto S, Aizawa K, Kimura A, Mizuno Y, Nagino T, Imai Y, Adachi N, Horikoshi M, and Nagai R (2003) Positive and Negative Regulation of the Cardiovascular Transcription Factor KLF5 by p300 and the Oncogenic Regulator SET through Interaction and Acetylation on the DNA-Binding Domain. Mol. Cell. Biol. 23:8528–8541PubMedCrossRefGoogle Scholar
- Sano H, Sudo T, Yokode M, Murayama T, Kataoka H, Takakura N, Nishikawa S, Nishikawa SI, and Kita T (2001) Functional blockade of platelet-derived growth factor receptor-β but not of receptor-α prevents vascular smooth muscle cell accumulation in fibrous cap lesions in Apolipoprotein E-deficient mice. Circulation 103:2955–2960PubMedGoogle Scholar
- SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW, Michel TM, Gimbrone MA, Jr., Garcia-Cardena G, and Jain MK (2004) KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J. Exp. Med. 199:1305–1315PubMedCrossRefGoogle Scholar
- Shindo T, Manabe I, Fukushima Y, Tobe K, Aizawa K, Miyamoto S, Kawai-Kowase K, Moriyama N, Imai Y, Kawakami H, Nishimatsu H, Ishikawa T, Suzuki T, Morita H, Maemura K, Sata M, Hirata Y, Komukai M, Kagechika H, Kadowaki T, Kurabayashi M, and Nagai R (2002) Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling. Nat Med 8:856–863PubMedGoogle Scholar
- Shinoda Y, Ogata N, Higashikawa A, Manabe I, Shindo T, Yamada T, Kugimiya F, Ikeda T, Kawamura N, Kawasaki Y, Tsushima K, Takeda N, Nagai R, Hoshi K, Nakamura K, Chung Ui, and Kawaguchi H (2008) Kruppel-like factor 5 causes cartilage degradation through trans-activation of matrix metalloproteinase 9. J. Biol. Chem. 283:24682–24689PubMedCrossRefGoogle Scholar
- Thomas JA, Deaton RA, Hastings NE, Shang Y, Moehle CW, Eriksson UJ, Topouzis S, Wamhoff BR, Blackman BR, and Owens GK (2008) PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerotic-prone flow patterns. Am. J. Physiol Heart Circ. Physiol 296:H442–H452PubMedCrossRefGoogle Scholar