Redox activation of JNK2 alpha 2 mediates thyroid hormone-stimulated proliferation of neonatal murine cardiomyocytes

• Type of Material: Article
• Authors: Lin Tan, Emory University; Nikolay Bogush, Emory University; Hussain Naib, Emory University; Jennifer Perry, Emory University; John W Calvert, Emory University; David I. K. Martin, Childrens Hosp; Robert M. Graham, Victor Chang Cardiac Research Institute; Nawazish Naqvi, Emory University; Ahsan Husain, Emory University
• Language: English
• Date: 2019-11-27
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-53705-1
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 17731
• End Page: 17731
• Grant/Funding Information: This work was supported by grants from the Department of Medicine, Emory University; the Carlyle Fraser Heart Center; Emory University Hospital Midtown; the NIH (HL079040, HL127726, HL098481, T32HL007745, HL092141, HL093579, HL094373, and HL113452); the American Heart Association (13SDG16460006; 17GRNT33670975); the Fondation Leducq Transatlantic Network; the National Health and Medical Research Council, Australia (APP1074386); the R.T. Hall estate; and the Australian Research Council Stem Cells Australia, Special Initiative in Stem Cell Science grant (SR1101002).
• Keywords: HYPERPLASIA; GENE-EXPRESSION; GROWTH; Science & Technology - Other Topics; RECEPTOR; HEART REGENERATION; PROPYLTHIOURACIL; BINUCLEATION; HYPERTROPHY; Science & Technology; ROLES; Multidisciplinary Sciences
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

Mitochondria-generated reactive oxygen species (mROS) are frequently associated with DNA damage and cell cycle arrest, but physiological increases in mROS serve to regulate specific cell functions. T3 is a major regulator of mROS, including hydrogen peroxide (H2O2). Here we show that exogenous thyroid hormone (T3) administration increases cardiomyocyte numbers in neonatal murine hearts. The mechanism involves signaling by mitochondria-generated H2O2 (mH2O2) acting via the redox sensor, peroxiredoxin-1, a thiol peroxidase with high reactivity towards H2O2 that activates c-Jun N-terminal kinase-2α2 (JNK2α2). JNK2α2, a relatively rare member of the JNK family of mitogen-activated protein kinases (MAPK), phosphorylates c-Jun, a component of the activator protein 1 (AP-1) early response transcription factor, resulting in enhanced insulin-like growth factor 1 (IGF-1) expression and activation of proliferative ERK1/2 signaling. This non-canonical mechanism of MAPK activation couples T3 actions on mitochondria to cell cycle activation. Although T3 is regarded as a maturation factor for cardiomyocytes, these studies identify a novel redox pathway that is permissive for T3-mediated cardiomyocyte proliferation—this because of the expression of a pro-proliferative JNK isoform that results in growth factor elaboration and ERK1/2 cell cycle activation.