Journal
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
Volume 106, Issue 1, Pages 289-299Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbiomolbio.2010.11.010
Keywords
Cardiomyocyte; Fetus; Programming; Terminal differentiation; Atrial natriuretic peptide; Tri-iodo-L-thyronine
Categories
Funding
- NICHD [P01 HD 34430]
- NHLBI [R21 HL093617, R01 HL102763, T32HL094294]
- Office of Research on Women's Health
- National Institute of Child Health and Human Development
- Oregon BIRCWH [HD043488]
- M. Lowell Edwards Endowment
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During fetal life the myocardium expands through replication of cardiomyocytes. In sheep, cardiomyocytes begin the process of becoming terminally differentiated at about 100 gestation days out of 145 days term. In this final step of development, cardiomyocytes become binucleated and stop dividing. The number of cells at birth is important in determining the number of cardiomyocytes for life. Therefore, the regulation of cardiomyocyte growth in the womb is critical to long term disease outcome. Growth factors that stimulate proliferation of fetal cardiomyocytes include angiotensin II, cortisol and insulin-like growth factor-1. Increased ventricular wall stress leads to short term increases in proliferation but longer-term loss of cardiomyocyte generative capacity. Two normally circulating hormones have been identified that suppress proliferation: atrial natriuretic peptide (ANP) and tri-iodo-L-thyronine (T-3). Atrial natriuretic peptide signals through the NPRA receptor that serves as a guanylate cyclase and signals through cGMP. ANP powerfully suppresses mitotic activity in cardiomyocytes in the presence of angiotensin II in culture. Addition of a cGMP analog has the same effect as ANP. ANP suppresses both the extracellular receptor kinases and the phosphoinositol-3 kinase pathways. T-3 also suppresses increased mitotic activity of stimulated cardiomyocytes but does so by increasing the cell cycle suppressant, p21, and decreasing the cell cycle activator, cyclin D1. (C) 2010 Elsevier Ltd. All rights reserved.
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