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KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis

Nature Medicine volume 21, pages 628–637 (2015)Cite this article

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A Corrigendum to this article was published on 04 February 2016

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Abstract

Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreERT2 ROSA floxed STOP eYFP Apoe−/− mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation–sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.

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Figure 1: Lineage tracing provides evidence for large populations of phenotypically modulated SMCs within lesions.
Figure 2: Ultrastructural and functional characteristics of phenotypically modulated SMCs.
Figure 3: SMCs within human coronary artery lesions express the macrophage marker CD68.
Figure 4: SMC-specific Klf4 deficiency results in decreased lesion size and increased indices of plaque stability.
Figure 5: KLF4 binds to >800 genes within SMCs in advanced atherosclerotic lesions.
Figure 6: KLF4-dependent effects in cholesterol-loaded, cultured SMCs.

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  • 12 August 2015

    In the version of this article initially published, the labels to the left of the two micrographs in Figure 2c are reversed. Also, in Figure 4g, MKi67, used as a cell proliferation marker, is misspelled. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We would like to acknowledge the valuable contributions of technicians M. McCanna and M. Bevard for their assistance in histological cutting and staining; R. Tripathi for assistance with cell culture work; J. Lannigan and M. Solga from the Flow Cytometry Core at the University of Virginia for their help designing flow cytometry panels and help running the cytometers; S. Guilot at the Advanced Microscopy Facility at University of Virginia for her help running the transmission electron microscope; J. Roithmayr, N. Hendley, M. Quetsch and M. Goodwin for their assistance in immunofluorescence image analysis; Y. Babiy for designing the cartoon in Supplementary Figure 6, and W. Evans for assistance in processing statistical analyses. We would also like to thank N. McGinn from the Department of Pathology, University of Virginia Hospital for the de-identified coronary arteries specimens; C. Murray from the University of Washington for the coronary artery heart transplant specimen; S. Offermanns from the Max Planck Institute for the Myh11-CreERT2 mice; K. Kaestner for the Klf4fl/fl mice; G. Randolph for the LysMCre/Cre mice; and A. Berns from the Netherlands Cancer Institute, Amsterdam, Netherlands, for the transgenic tamoxifen-inducible Cre (ERT-Cre) recombinase mice. This work was supported by US National Institutes of Health R01 grants HL057353, HL098538 and HL087867 to G.K.O., HL112904 to A.C.S., as well as a pilot grant from AstraZeneca as part of a University of Virginia–AstraZeneca Research Alliance to G.K.O.; and Mid-Atlantic American Heart Association fellowship grants 11PRE7170008 and 13POST17080043 to L.S.S. and D.G., respectively.

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Authors and Affiliations

  1. Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA

    Laura S Shankman, Delphine Gomez, Olga A Cherepanova, Gabriel F Alencar, Ryan M Haskins, Pamela Swiatlowska, Alexandra A C Newman, Elizabeth S Greene, Brant Isakson & Gary K Owens

  2. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA

    Laura S Shankman, Brant Isakson & Gary K Owens

  3. Department of Surgery, University of Virginia, Charlottesville, Virginia, USA

    Morgan Salmon

  4. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA

    Gabriel F Alencar & Alexandra A C Newman

  5. Department of Pathology, University of Virginia, Charlottesville, Virginia, USA

    Ryan M Haskins

  6. Intercollegiate Faculty of Biotechnology, University of Gdansk, Gdansk, Poland

    Pamela Swiatlowska

  7. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Adam C Straub

  8. Division of Biology and Biomedical Sciences, Washington University, St. Louis, Missouri, USA

    Gwendalyn J Randolph

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  1. Laura S Shankman
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Contributions

L.S.S. conducted experiments; performed data analysis; generated most of the experimental mice; performed immunostaining, image analysis and flow cytometry; and was primary writer of the manuscript. D.G. performed in vitro ChIP analysis and conceived and performed all the ISH-PLA experiments. M.S. generated Tagln wild-type lacZ Apoe−/− mice, performed in vivo ChIP assays, and performed immunohistochemistry and data analysis. O.A.C. was involved in designing experiments and data analysis; assisted in image analysis, cell culture and animal experiments throughout the project. A.C.S. and B.I. participated in designing the immuno-transmission electron microscopy protocol and analysis of images. R.M.H. performed the MSC immunostaining and image analysis, and the Klf4 ChIP-seq; conducted MSC differentiation experiments; and helped design cartoons. G.F.A. conducted data analysis of ChIP-seq experiments. P.S. assisted in cell culture experiments and analysis of data. A.A.C.N. performed PDGFβR staining and analysis. E.S.G. assisted in animal experiments, conducted statistical analyses and performed immunohistochemistry and data analysis. L.S.S., D.G., M.S., O.A.C., E.S.G., B.I., G.J.R. and G.K.O. participated in making final manuscript revisions. G.K.O. supervised the entire project and had a major role in experimental design, data interpretation, and writing the manuscript.

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Correspondence to Gary K Owens.

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Shankman, L., Gomez, D., Cherepanova, O. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 21, 628–637 (2015). https://doi.org/10.1038/nm.3866

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