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Author Notes:

Nawazish Naqvi, Email: nnaqvi@emory.edu

Conceptualization, N.N. and A.H.; investigation, N.B., L.T., E.N., J.W.C., and N.N.; data analysis, N.B., L.T., E.N., J.W.C., N.N., and A.H.; writing—original draft, A.H. and N.N.; writing—review and editing, A.H., N.N., R.M.G., and W.R.T.; illustrations, A.H.; supervision and project administration, A.H. and N.N.; funding acquisition, A.H., N.N., and W.R.T. ultimately, both NB and LT contributed equally to this study; the order of the co-first authors was determined by who the study was first assigned to, as agreed to by these authors at the beginning of the collaboration.

We thank Jack Kearse for photography of mouse hearts. 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, National Health and Medical Research Council, Australia (APP1074386), J. Hill Development Fund, R.T. Hall estate, and the Australian Research Council Stem Cells Australia Special Initiative in Stem Cell Science grant (SR1101002).

A.H., and N.N. are inventors on a patent arising from this work (WO2020037076). The other authors declare no competing interests.

Subjects:

Research Funding:

This article was funded by National Institutes of Health (T32HL007745, HL127726, HL094373), Fondation Leducq, the Fondation Leducq Transatlantic Network, National Health and Medical Research Council (APP1074386), the Australian Research Council Stem Cells Australia Special Initiative in Stem Cell Science grant (SR1101002), R.T. Hall estate, Australia, American Heart Association (17GRNT33670975) and J. Hill Development Fund.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PERCUTANEOUS CORONARY INTERVENTION
  • CARDIOMYOCYTE DNA-SYNTHESIS
  • MYOCARDIAL-INFARCTION
  • CARDIAC-FUNCTION
  • HEART REGENERATION
  • CELL-DEATH
  • ACTIVATION
  • MECHANISMS
  • EXPRESSION
  • RECEPTORS

Remuscularization with triiodothyronine and beta(1)-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling

Journal Title:

SCIENTIFIC REPORTS

Volume:

Volume 12, Number 1

Publisher:

, Pages 8852-8852

Type of Work:

Article | Final Publisher PDF

Abstract:

Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β1-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.

Copyright information:

© The Author(s) 2022

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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