Krüppel-like Factor 4 is Induced by Rapamycin and Mediates the Anti-proliferative Effect of Rapamycin in Rat Carotid Arteries After Balloon Injury

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2011 Oct 25

PMID 22017667

Citations 22

Authors

Ying Wang

Beilei Zhao

Yi Zhang

Zhihui Tang

Qiang Shen

Youyi Zhang

Weizhen Zhang

Jie Du

Shu Chien

Nanping Wang

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: The transcription factor, Krüppel-like factor 4 (KLF4), plays an important role in regulating the proliferation of vascular smooth muscle cells. This study aimed to examine the effect of rapamycin on the expression of KLF4 and the role of KLF4 in arterial neointimal formation.

Experimental Approach: Expression of KLF4 was monitored using real-time PCR and immunoblotting in cultured vascular smooth muscle cells. and in rat carotid arteries in vivo after balloon injury. Adenovirus-mediated overexpression and siRNA-mediated knockdown of KLF4 were used to examine the role of KLF4 in mediating the anti-proliferative role of rapamycin . KLF4-regulated genes were identified using cDNA microarray.

Key Results: Rapamycin induced the expression of KLF4 in vitro and in vivo. Overexpression of KLF4 inhibited cell proliferation and the activity of mammalian target of rapamycin (mTOR) and its downstream pathways, including 4EBP-1 and p70S6K in vascular smooth muscle cells and prevented the neointimal formation in the balloon-injured arteries. KLF4 up-regulated the expression of GADD45β, p57(kip2) and p27(kip1) . Furthermore, knockdown of KLF4 attenuated the anti-proliferative effect of rapamycin both in vitro and in vivo.

Conclusions And Implications: KLF4 plays an important role in mediating the anti-proliferative effect of rapamycin in VSMCs and balloon-injured arteries. Thus, it is a potential target for the treatment of proliferative vascular disorders such as restenosis after angioplasty.

Citing Articles

Krüppel-like factors: potential roles in blood-brain barrier dysfunction and epileptogenesis.

Santos A, Carona A, Ettcheto M, Camins A, Falcao A, Fortuna A Acta Pharmacol Sin. 2024; 45(9):1765-1776.

PMID: 38684799 PMC: 11335766. DOI: 10.1038/s41401-024-01285-w.

Overexpression of KLF4 Suppresses Pulmonary Fibrosis through the HIF-1α/Endoplasmic Reticulum Stress Signaling Pathway.

Wei S, Qi F, Wu Y, Liu X Int J Mol Sci. 2023; 24(18).

PMID: 37762310 PMC: 10530972. DOI: 10.3390/ijms241814008.

Elevated circulating Krüppel-like factor 4 level as a novel independent marker of the proatherogenic risk in patients with psoriasis: a preliminary study.

Baran A, Krahel J, Kaminski T, Krawiel M, Maciaszek M, Flisiak I Postepy Dermatol Alergol. 2022; 38(6):1023-1031.

PMID: 35126010 PMC: 8802956. DOI: 10.5114/ada.2020.98560.

Circadian rhythm influences induction of trained immunity by BCG vaccination.

de Bree L, Mourits V, Koeken V, Moorlag S, Janssen R, Folkman L J Clin Invest. 2020; 130(10):5603-5617.

PMID: 32692732 PMC: 7641012. DOI: 10.1172/JCI133934.

Endothelial mechanobiology.

He M, Martin M, Marin T, Chen Z, Gongol B APL Bioeng. 2020; 4(1):010904.

PMID: 32095737 PMC: 7032971. DOI: 10.1063/1.5129563.

References

Agrotis A, Kanellakis P, Kostolias G, Di Vitto G, Wei C, Hannan R . Proliferation of neointimal smooth muscle cells after arterial injury. Dependence on interactions between fibroblast growth factor receptor-2 and fibroblast growth factor-9. J Biol Chem. 2004; 279(40):42221-9. DOI: 10.1074/jbc.M408121200. View

Jawien A, Bowen-Pope D, Lindner V, Schwartz S, Clowes A . Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992; 89(2):507-11. PMC: 442880. DOI: 10.1172/JCI115613. View

Morris R, Cao W, Huang X, Gregory C, Billingham M, Rowan R . Rapamycin (Sirolimus) inhibits vascular smooth muscle DNA synthesis in vitro and suppresses narrowing in arterial allografts and in balloon-injured carotid arteries: evidence that rapamycin antagonizes growth factor action on immune and nonimmune.... Transplant Proc. 1995; 27(1):430-1. View

Shagdarsuren E, Djalali-Talab Y, Aurrand-Lions M, Bidzhekov K, Liehn E, Imhof B . Importance of junctional adhesion molecule-C for neointimal hyperplasia and monocyte recruitment in atherosclerosis-prone mice-brief report. Arterioscler Thromb Vasc Biol. 2009; 29(8):1161-3. DOI: 10.1161/ATVBAHA.109.187898. View

Alder J, Georgantas 3rd R, Hildreth R, Kaplan I, Morisot S, Yu X . Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol. 2008; 180(8):5645-52. PMC: 3074963. DOI: 10.4049/jimmunol.180.8.5645. View

Raines E . PDGF and cardiovascular disease. Cytokine Growth Factor Rev. 2004; 15(4):237-54. DOI: 10.1016/j.cytogfr.2004.03.004. View

Segre J, Bauer C, Fuchs E . Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet. 1999; 22(4):356-60. DOI: 10.1038/11926. View

Yet S, McANulty M, Folta S, Yen H, Yoshizumi M, HSIEH C . Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J Biol Chem. 1998; 273(2):1026-31. DOI: 10.1074/jbc.273.2.1026. View

Wang N, Verna L, Chen N, Chen J, Li H, Forman B . Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem. 2002; 277(37):34176-81. DOI: 10.1074/jbc.M203436200. View

10.

Bayes-Genis A, Campbell J, Carlson P, Holmes Jr D, Schwartz R . Macrophages, myofibroblasts and neointimal hyperplasia after coronary artery injury and repair. Atherosclerosis. 2002; 163(1):89-98. DOI: 10.1016/s0021-9150(01)00771-7. View

11.

Serruys P, Luijten H, Beatt K, Geuskens R, de Feyter P, van den Brand M . Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation. 1988; 77(2):361-71. DOI: 10.1161/01.cir.77.2.361. View

12.

King K, Iyemere V, Weissberg P, Shanahan C . Krüppel-like factor 4 (KLF4/GKLF) is a target of bone morphogenetic proteins and transforming growth factor beta 1 in the regulation of vascular smooth muscle cell phenotype. J Biol Chem. 2003; 278(13):11661-9. DOI: 10.1074/jbc.M211337200. View

13.

Marks A . Cellular functions of immunophilins. Physiol Rev. 1996; 76(3):631-49. DOI: 10.1152/physrev.1996.76.3.631. View

14.

Liu Y, Sinha S, McDonald O, Shang Y, Hoofnagle M, Owens G . Kruppel-like factor 4 abrogates myocardin-induced activation of smooth muscle gene expression. J Biol Chem. 2004; 280(10):9719-27. DOI: 10.1074/jbc.M412862200. View

15.

Feinberg M, Wara A, Cao Z, Lebedeva M, Rosenbauer F, Iwasaki H . The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J. 2007; 26(18):4138-48. PMC: 2230668. DOI: 10.1038/sj.emboj.7601824. View

16.

Adam P, Regan C, Hautmann M, Owens G . Positive- and negative-acting Kruppel-like transcription factors bind a transforming growth factor beta control element required for expression of the smooth muscle cell differentiation marker SM22alpha in vivo. J Biol Chem. 2000; 275(48):37798-806. DOI: 10.1074/jbc.M006323200. View

17.

Razuvaev A, Lund K, Roy J, Hedin U, Caidahl K . Noninvasive real-time imaging of intima thickness after rat carotid artery balloon injury using ultrasound biomicroscopy. Atherosclerosis. 2008; 199(2):310-6. DOI: 10.1016/j.atherosclerosis.2007.11.035. View

18.

Marx S, Marks A . Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation. 2001; 104(8):852-5. DOI: 10.1161/01.cir.104.8.852. View

19.

Tang Z, Wang Y, Fan Y, Zhu Y, Chien S, Wang N . Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries. Circulation. 2008; 118(7):764-72. DOI: 10.1161/CIRCULATIONAHA.107.761932. View

20.

Nobuyoshi M, Kimura T, Nosaka H, Mioka S, Ueno K, Yokoi H . Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol. 1988; 12(3):616-23. DOI: 10.1016/s0735-1097(88)80046-9. View