title: Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes.
abstract: Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.
authors.affiliation: Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Amaresh K
authors.initials: AK
authors.lastname: Ranjan
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Richard K
authors.initials: RK
authors.lastname: Cheng
authors.forename: Rina J
authors.initials: RJ
authors.lastname: Kara
authors.forename: Romit
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Gabriela
authors.initials: G
authors.lastname: Guzman-Martinez
authors.forename: Javier
authors.initials: J
authors.lastname: Sanz
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Garcia
authors.forename: Hina W
authors.initials: HW
authors.lastname: Chaudhry
mesh_terms: D000818:Animals; D056751:Cyclin A2 / Q000502:physiology*; D048749:Cytokinesis; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology*; D012038:Regeneration; D013552:Swine
chemical_list: D056751:Cyclin A2