Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family

Enzo R. Porrello, Ahmed I. Mahmoud, Emma Simpson, Brett A. Johnson, David Grinsfelder, Diana Canseco, Pradeep P. Mammen, Beverly A. Rothermel, Eric N. Olson, Hesham A. Sadek

Research output: Contribution to journalArticle

365 Scopus citations

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 mostcommon antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-oldmice and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal heartmounted 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.

Original languageEnglish (US)
Pages (from-to)187-192
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
StatePublished - Jan 2 2013

Keywords

  • Cardiac regenerative window
  • Cardiomyocyte cell cycle
  • Posttranscriptional regulation

ASJC Scopus subject areas

  • General

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