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Dissecting the role of myeloid and mesenchymal fibroblasts in age-dependent cardiac fibrosis

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Abstract

Aging is associated with increased cardiac interstitial fibrosis and diastolic dysfunction. Our previous study has shown that mesenchymal fibroblasts in the C57BL/6J (B6J) aging mouse heart acquire an inflammatory phenotype and produce higher levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) secreted by these aged fibroblasts promotes leukocyte uptake into the heart. Some of the monocytes that migrate into the heart polarize into M2a macrophages/myeloid fibroblasts. The number of activated mesenchymal fibroblasts also increases with age, and consequently, both sources of fibroblasts contribute to fibrosis. Here, we further investigate mechanisms by which inflammation influences activation of myeloid and mesenchymal fibroblasts and their collagen synthesis. We examined cardiac fibrosis and heart function in three aged mouse strains; we compared C57BL/6J (B6J) with two other strains that have reduced inflammation via different mechanisms. Aged C57BL/6N (B6N) hearts are protected from oxidative stress and fibroblasts derived from them do not develop an inflammatory phenotype. Likewise, these mice have preserved diastolic function. Aged MCP-1 null mice on the B6J background (MCP-1KO) are protected from elevated leukocyte infiltration; they develop moderate but reduced fibrosis and diastolic dysfunction. Based on these studies, we further delineated the role of resident versus monocyte-derived M2a macrophages in myeloid-dependent fibrosis and found that the number of monocyte-derived M2a (but not resident) macrophages correlates with age-related fibrosis and diastolic dysfunction. In conclusion, we have found that ROS and inflammatory mediators are necessary for activation of fibroblasts of both developmental origins, and prevention of either led to better functional outcomes.

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Acknowledgements

This research was supported by NIH Grant R01HL089792 (MLE), a Medallion Foundation Grant (KAC), and the Hankamer Foundation. We would like to thank Dr. Jeffrey Crawford for conducting the monocyte chemoattractant assay. We thank Thuy Pham and Dorellyn Lee for excellent technical assistance.

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  1. Division of Cardiovascular Sciences and the DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, M.S. BCM620, Houston, TX, 77030, USA

    JoAnn Trial, Celia Pena Heredia, George E. Taffet, Mark L. Entman & Katarzyna A. Cieslik

  2. Houston Methodist, Houston, TX, USA

    Mark L. Entman

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  1. JoAnn Trial
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Trial, J., Heredia, C.P., Taffet, G.E. et al. Dissecting the role of myeloid and mesenchymal fibroblasts in age-dependent cardiac fibrosis. Basic Res Cardiol 112, 34 (2017). https://doi.org/10.1007/s00395-017-0623-4

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