Positive-Feedback Regulation Loop for the Loss of Cell Division and Binucleation Shortly after Birth in Cardiomyocytes

Abstract

AbstractShortly after birth, mammalian cardiomyocytes irreversibly exit from the cell cycle and become terminally differentiated. The cellular mechanisms responsible for the cessation of cell division and terminal differentiation of cardiomyocytes soon after birth have intrigued developmental biologists as well as cardiovascular physicians, but the genetic cues for the irreversible exit from the cell cycle soon after birth remain largely unknown. Here we examined whether and if so how oxidative stress to mammalian hearts during fetal-toneonatal transition produces changes in the proliferative activity and terminal differentiation of cardiomyocytes. Scavenging of reactive oxygen species (ROS) during fetal-to-neonatal transition, especially after birth, resulted in an increase in the proliferative activity and a decrease in the ratio of binucleated cardiomyocytes. Exposure to ROS in cultured cardiomyocytes increased the activity of p38 MAPK and the expression of connexin43 (Cx43). Not only down-regulation of Cx43 using siRNA but also the inhibition of p38 MAPK activity resulted in a significant decrease in the production of ROS in cardiomyocytes, suggesting that the signaling pathway ROS–p38 MAPK–Cx43 (especially, Cx43 at mitochondria, mtCx43) constituted a closed regulatory system with positive-feedback. In addition, continuous scavenging of ROS or suppression of p38 MAPK activity for 4 days after birth resulted in a significant decrease in the expression of mtCx43 and in the number of binucleated cardiomyocytes. This study demonstrated that the ROS-induced formation of a positive-feedback loop ROS–p38 MAPK–mtCx43 for the sustained activation of p38 MAPK soon after birth possibly contributes to the loss of cell division and binucleation in mammalian cardiomyocytes.Keywordsperinatal oxidative stressreactive oxygen speciesconnexin43positive-feedback loopbinucleation