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Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia–reperfusion injury

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Abstract

Ischemic cardiac injury is the main contributor to heart failure, and the regenerative capacity of intrinsic stem cells plays an important role in tissue repair after injury. However, stem cells in aged individuals have reduced regenerative potential and aged tissues lack the capacity to renew. Growth differentiation factor 11 (GDF11), from the activin-transforming growth factor β superfamily, has been shown to promote stem cell activity and rejuvenation. We carried out non-invasive targeted delivery of the GDF11 gene to the heart using ultrasound-targeted microbubble destruction (UTMD) and cationic microbubble (CMB) to investigate the ability of GDF11 to rejuvenate the aged heart and improve tissue regeneration after injury. Young (3 months) and old (21 months) mice were used to evaluate the expression of GDF11 mRNA in the myocardium at baseline and after ischemia/reperfusion (I/R) and myocardial infarction. GDF11 expression decreased with age and following myocardial injury. UTMD-mediated delivery of the GDF11 plasmid to the aged heart after I/R injury effectively and selectively increased GDF11 expression in the heart, and improved cardiac function and reduced infarct size. Over-expression of GDF11 decreased senescence markers, p16 and p53, as well as the number of p16+ cells in old mouse hearts. Furthermore, increased proliferation of cardiac stem cell antigen 1 (Sca-1+) cells and increased homing of endothelial progenitor cells and angiogenesis in old ischemic hearts occurred after GDF11 over-expression. Repetitive targeted delivery of the GDF11 gene via UTMD can rejuvenate the aged mouse heart and protect it from I/R injury.

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Acknowledgements

We thank Dr. Leigh Botly for help with manuscript preparation and editing. This work was supported by a Foundation grant from the Canadian Institutes of Health Research (332652) to R-KL. R-KL holds a Tier 1 Canada Research Chair in Cardiac Regeneration.

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    Authors and Affiliations

    1. Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China

      Guo-Qing Du & Jia-Wei Tian

    2. Department of Genetics, Harbin Medical University, Harbin, China

      Jie Wu

    3. Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China

      Zheng-Bo Shao

    4. Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Canada

      Guo-Qing Du, Zheng-Bo Shao, Jie Wu, Wen-Juan Yin, Shu-Hong Li, Jun Wu, Richard D. Weisel & Ren-Ke Li

    5. Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada

      Ren-Ke Li

    6. Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada

      Richard D. Weisel & Ren-Ke Li

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    1. Guo-Qing Du
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    G.-Q. Du and Z.-B. Shao contributed equally.

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    Du, GQ., Shao, ZB., Wu, J. et al. Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia–reperfusion injury. Basic Res Cardiol 112, 7 (2017). https://doi.org/10.1007/s00395-016-0593-y

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