1. DUSP5 expression in left ventricular cardiomyocytes of young hearts regulates thyroid hormone (T3)-induced proliferative ERK1/2 signaling
- Author
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Lin Tan, Ankan Gupta, Siiri E. Iismaa, Nawazish Naqvi, John W. Calvert, David I. K. Martin, Hussain Naib, Ahsan Husain, Robert M. Graham, Ramani Ramchandran, Ebrahim Faizullabhoy, and Nikolay Bogush
- Subjects
Cell biology ,medicine.medical_specialty ,Cell signaling ,MAP Kinase Signaling System ,Heart Ventricles ,Science ,Phosphatase ,Mice, Transgenic ,Article ,Gene Expression Regulation, Enzymologic ,Mice ,Internal medicine ,medicine ,Animals ,Myocytes, Cardiac ,Receptor ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Multidisciplinary ,biology ,Myocardium ,Thyroid ,Cardiac muscle ,Cardiovascular biology ,Apex (geometry) ,Endocrinology ,medicine.anatomical_structure ,Mitogen-activated protein kinase ,biology.protein ,Dual-Specificity Phosphatases ,Triiodothyronine ,Medicine ,Cell signalling ,Hormone - Abstract
A developmental surge in thyroid hormone (T3) after postnatal day-10 (P10), in mice, results in a burst of cardiomyocyte proliferation. This finding remains controversial, which could arise from perceived homogeneity of myocardial sampling for immunoblotting and immunohistochemical studies, or from differences in enzymatic digestion efficiency for cardiomyocyte isolation used to determine total ventricular cardiomyocyte numbers. Using a highly efficient (>97%) method for cardiomyocyte isolation, we show that exogenous T3 administered in vivo to post-neonatal (after postnatal P6) mice increased cardiomyocyte numbers. Using S- and M-phase markers, and lineage-tracing tools to assay for cell cycle activation and cytokinesis, respectively, we show that the T3-mediated increase in cardiomyocytes is confined to cells of the left ventricular (LV) apex; such spatial heterogeneity also being observed during normal development, which might confound substantiation of developmental increases in cardiomyocyte proliferation. In these apical cardiomyocytes, T3 stimulates proliferative ERK1/2 signaling, whereas those in the LV base are tonically inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. In P21 Dusp5–/– mice, cardiomyocyte endowment and LV mass are increased relative to age-matched wild-type controls, suggesting that DUSP5 regulates early heart growth. Identification of mechanisms regulating cardiomyocyte proliferation may allow development of cardiac regenerative therapies.
- Published
- 2020