title: Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia-reperfusion injury.
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.
authors.affiliation: Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China.|Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Du
authors.affiliation: Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.|Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.
authors.forename: Zheng-Bo
authors.initials: ZB
authors.lastname: Shao
authors.affiliation: Department of Genetics, Harbin Medical University, Harbin, China.|Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.|Department of Pathology, Shanxi Medical University, Taiyuan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Yin
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Department of Ultrasound, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China. jiaweitian@126.com.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Tian
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College St., Toronto, ON, M5G 1L7, Canada. renkeli@uhnresearch.ca.|Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada. renkeli@uhnresearch.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000235:genetics*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods; D055412:Growth Differentiation Factors / Q000008:administration & dosage / Q000235:genetics*; D006321:Heart / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D015428:Myocardial Reperfusion Injury; D009206:Myocardium; D012038:Regeneration; D059467:Transcriptome
chemical_list: D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors
keywords: GDF11; Heart; Ischemia–reperfusion; Regeneration; Rejuvenation