title: Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs.
abstract: We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit(+) CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit(+) CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit(+) CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit(+) CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit(+) CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit(+) CSCs compared with MI hearts engrafted with control siRNA-treated c-kit(+) CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFP-infected c-kit(+) CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit(+) CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit(+) CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit(+) CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.
authors.affiliation: Department of Medicine, Rhode Island Hospital, Brown Medical School, Brown University, Providence, Rhode Island;
authors.forename: Ling X
authors.initials: LX
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
authors.forename: Megan
authors.initials: M
authors.lastname: DeNicola
authors.affiliation: Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
authors.forename: Xin
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
authors.forename: Julio
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Medicine, Rhode Island Hospital, Brown Medical School, Brown University, Providence, Rhode Island; tzhao@bu.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tina Zhao
authors.affiliation: Department of Medicine, Rhode Island Hospital, Brown Medical School, Brown University, Providence, Rhode Island;
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
authors.forename: Paul Y
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Rhode Island Hospital, Brown Medical School, Brown University, Providence, Rhode Island.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Medicine, University of Cincinnati, Cincinnati, Ohio;
authors.forename: Yaoliang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, Rhode Island;
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034622:RNA Interference; D020127:Recovery of Function; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000201:enzymology*; D013318:Stroke Volume; D013997:Time Factors; D014162:Transfection; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D015415:Biomarkers; D019394:Ki-67 Antigen; D019009:Proto-Oncogene Proteins c-kit; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: HDAC4; heart; myocardial infarction; regeneration; stem cells