title: Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family.
abstract: We recently identified a brief time period during postnatal development when the mammalian heart retains significant regenerative potential after amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-old mice and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal heart mounted a robust regenerative response, through proliferation of preexisting cardiomyocytes, resulting in full functional recovery within 21 d. Moreover, we show that the miR-15 family of microRNAs modulates neonatal heart regeneration through inhibition of postnatal cardiomyocyte proliferation. Finally, we demonstrate that inhibition of the miR-15 family from an early postnatal age until adulthood increases myocyte proliferation in the adult heart and improves left ventricular systolic function after adult MI. We conclude that the neonatal mammalian heart can regenerate after myocardial infarction through proliferation of preexisting cardiomyocytes and that the miR-15 family contributes to postnatal loss of cardiac regenerative capacity.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Mahmoud
authors.forename: Emma
authors.initials: E
authors.lastname: Simpson
authors.forename: Brett A
authors.initials: BA
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Grinsfelder
authors.forename: Diana
authors.initials: D
authors.lastname: Canseco
authors.forename: Pradeep P
authors.initials: PP
authors.lastname: Mammen
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000601:surgery; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D007091:Image Processing, Computer-Assisted; D007211:Indoles; D008026:Ligation; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism* / Q000502:physiology; D009203:Myocardial Infarction / Q000209:etiology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000150:complications*; D032383:Myocytes, Cardiac / Q000502:physiology; D012038:Regeneration / Q000502:physiology*
chemical_list: D005697:Galactosides; D007211:Indoles; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside