Regulation of the cardiomyocyte population in the developing heart

Abstract

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 (T3). 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 analogue has the same effect as ANP. ANP suppresses both the extracellular receptor kinases and the phosphoinositol 3 kinase pathways. T3 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.

Impaired Cardiovascular Structure and Function in Adult Survivors of Severe Acute Malnutrition

“…24 Our results are thus compatible with abnormal cardiac development among SAM survivors during fetal and postnatal plastic periods.…”

“…These findings are relevant to large numbers of people previously exposed to malnutrition across the world. Such effects could originate in utero, 24,25 but may also result from, or be exacerbated by, the malnutrition insult in early childhood.…”

Thyroid hormones in fetal growth and prepartum maturation

“…Thyroid hormones are also essential for the normal maturation of cardiomyocytes and the cardiovascular system (Thornburg et al 2011). They promote a switch from proliferation to hypertrophy and differentiation of the cardiomyocytes both at term and earlier in gestation (Chattergoon et al 2012a,b).…”

The Cardiomyocyte Cell Cycle in Hypertrophy, Tissue Homeostasis, and Regeneration

“…While the timing of binucleation in mammals correlates highly with the onset of cardiomyocyte cell cycle withdrawal, the percentage of binucleation varies amongst mammalian species:~90 % in rodents (Li et al 1996;Soonpaa et al 1996),~70 % in sheep (Burrell et al 2003;Thornburg et al 2011), and~23-57 % in humans (Olivetti et al 1996;Schmid and Pfitzer 1985;Kajstura et al 2012). What accounts for interspecies differences in the percentage of binucleated cardiomyocytes is unknown.…”