Redox regulation of cardiomyocyte proliferation: The Ucp2 Avenue

Abstract

A major block to cardiac regeneration is the low capacity of cardiomyocytes (CMs) to self-renew. In mice, while adult heart exhibit limited regenerative response after injury, neonates show efficient repair thanks to robust CM proliferation. Recent studies have shown that exposure to 20% oxygen at birth leads to CM increased reliance on OXPHOS for ATP production. This metabolic switch triggers increased production of mitochondrial ROS, molecules that participate in CM cell-cycle arrest. Thus, regulating mtROS production stands as a promising avenue to allow CM proliferation and cardiac regeneration. In this context, the Uncoupling Protein 2 (Ucp2) represents a key player as it regulates cell proliferation in several models through modulation of mtROS production. Our goal is to investigate whether Ucp2 can regulate CMs proliferation and heart regeneration through modulation of their redox state. Ucp2 expression profile was assessed in mouse heart from fetal to adult stages. Using CMs models in which Ucp2 expression or function is genetically (Ucp2-/-) or chemically (genipin) targeted, we then addressed its role in neonatal CMs proliferation, ROS levels, metabolic activity, and DNA damage. While Ucp2 is expressed at low levels during development, its expression is upregulated at birth. It then decreases from P7 to become barely detectable in the adult, thus correlating with the heart regenerative period. We show that Ucp2 loss or inhibition in neonatal CMs leads to a reduction of mitochondrial respiration, together with an increase of ROS levels, DNA damage and activation of p38MAPK signaling pathway. As expected, this is correlated with a significant reduction of neonatal cardiomyocytes proliferation. We demonstrate that Ucp2, through modulation of neonatal CMs mitochondrial activity and redox state plays a key role in the maintenance of their proliferation. We currently assess the consequences of Ucp2 gain of function in the proliferative capacity of adult CMs.