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Stat3β mitigates development of atherosclerosis in apolipoprotein E-deficient mice

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Abstract

The transcription factor Stat3 is an activator of systemic inflammatory genes. Two isoforms of Stat3 are generated by alternative splicing, Stat3α and Stat3β. The β isoform lacks the transactivation domain but retains other functions, including dimerization and DNA binding. Stat3β-deficient mice exhibit elevated expression of systemic inflammatory genes and are hyperresponsive to lipopolysaccharide, suggesting that Stat3β functions predominantly as a suppressor of systemic inflammation. To test whether Stat3β deficiency would provoke pathologic effects associated with chronic inflammation, we asked whether selective removal of Stat3β would exacerbate the development of atherosclerosis in apolipoprotein E-deficient mice. In apoE−/−Stat3β−/− mice atherosclerotic plaque formation was significantly enhanced relative to apoE−/−Stat3β+/+ controls. The ability of Stat3β deficiency to promote atherosclerosis was more pronounced in female mice, but could be unmasked in males by feeding a high fat diet. Infiltrating macrophages were not increased in aortas of apoE−/−Stat3β−/− mice. In contrast, the proportion of pro-inflammatory TH17 cells was significantly elevated in aortic infiltrates from apoE−/−Stat3β−/− mice, relative to paired apoE−/−Stat3β+/+ littermates. These observations indicate that Stat3β can suppress pathologic sequelae associated with chronic inflammation. Our findings further suggest that in Stat3β-deficient mice the unopposed action of Stat3α may enhance atherogenesis in part by promoting differentiation of TH17 cells.

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Acknowledgements and disclosure statement

We are grateful to Dominic Dordai for expert technical support and Karen Fox-Talbot for preparation and staining of aortic root samples. The work was supported by National Institutes of Health grant HL073971 and by a gift to the Johns Hopkins Institute for Cell Engineering. J.L. was supported in part by National Institute of General Medical Sciences training grant 5T32GM008752. The authors have no commercial or other associations that would pose a conflict of interest in connection with this manuscript.

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Authors and Affiliations

  1. Department of Molecular Biology and Genetics and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Room 619, 733 N. Broadway, Baltimore, MD, 21205, USA

    Jihyun Lee & Stephen Desiderio

  2. Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    William M. Baldwin III

  3. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Chih-Yuan Lee

  4. Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA

    Jihyun Lee

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  1. Jihyun Lee
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Correspondence to Stephen Desiderio.

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Lee, J., Baldwin, W.M., Lee, CY. et al. Stat3β mitigates development of atherosclerosis in apolipoprotein E-deficient mice. J Mol Med 91, 965–976 (2013). https://doi.org/10.1007/s00109-013-1013-5

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