DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling

• Type of Material: Article
• Authors: Nikolay Bogush, Emory University; Lin Tan, Emory University; Hussain Naib, Emory University; Ebrahim Faizullabhoy, Emory University; John Calvert, Emory University; Siiri Iismaa, Victor Chang Cardiac Research Institute; Ankan Gupta, Medical College of Wisconsin; Ramani Ramchandran, Medical College of Wisconsin; David I. K. Martin, Children’s Hospital Oakland Research Institute; Robert M. Graham, Victor Chang Cardiac Research Institute; Ahsan Husain, Emory University; Nawazish Naqvi, Emory University
• Language: English
• Date: 2020-12-14
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-020-78825-x
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 10
• Issue: 1
• Start Page: 21918
• End Page: 21918
• 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, HL113452, HL123338 and T32HL007745), the American Heart Association (13SDG16460006; 17GRNT33670975), the Fondation Leducq Transatlantic Network, National Health and Medical Research Council, Australia (APP1074386), R.T. Hall estate, the Australian Research Council Stem Cells Australia, Special Initiative in Stem Cell Science grant (SR1101002) and the Department of Pediatrics, Children’s Research Institute, Medical College of Wisconsin.
• Keywords: Science & Technology; Science & Technology - Other Topics; Multidisciplinary Sciences; RECEPTORS; KINASE PHOSPHATASES MKPS; GROWTH; NUMBER
• Research Categories: Health Sciences, General

Abstract

Cardiomyocytes of newborn mice proliferate after injury or exposure to growth factors. However, these responses are diminished after postnatal day-6 (P6), representing a barrier to building new cardiac muscle in adults. We have previously shown that exogenous thyroid hormone (T3) stimulates cardiomyocyte proliferation in P2 cardiomyocytes, by activating insulin-like growth factor-1 receptor (IGF-1R)-mediated ERK1/2 signaling. But whether exogenous T3 functions as a mitogen in post-P6 murine hearts is not known. Here, we show that exogenous T3 increases the cardiomyocyte endowment of P8 hearts, but the proliferative response is confined to cardiomyocytes of the left ventricular (LV) apex. Exogenous T3 stimulates proliferative ERK1/2 signaling in apical cardiomyocytes, but not in those of the LV base, which is inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. Developmentally, between P7 and P14, DUSP5 expression increases in the myocardium from the LV base to its apex; after this period, it is uniformly expressed throughout the LV. In young adult hearts, exogenous T3 increases cardiomyocyte numbers after DUSP5 depletion, which might be useful for eliciting cardiac regeneration.