Effects of cortisol on cardiac myocytes and on expression of cardiac genes in fetal sheep

Abstract

In 17 fetal sheep aged 129 days, the effects of large-dose infusions of cortisol (72.1 mg/day for 2-3 days) on proliferation, binucleation, and hypertrophy of cardiac myocytes, cardiac expression of angiotensinogen, angiotensin receptor subtypes 1 and 2, Glut-1, glucocorticoid and mineralocorticoid receptors, proteins of the MAPK pathways and calcineurin were studied. Cortisol levels were 8.7 +/- 2.3 nM (SE) in 8 control and 1,028 +/- 189 nM in 9 treated fetuses (P < 0.001). Cortisol had no effect on myocyte binucleation. Left ventricular free wall (LVFW) uni- and binucleated myocytes were larger in cortisol-treated fetuses (P < 0.001, P < 0.05). Cortisol-treated fetuses had higher right ventricular free wall (RVFW) and LVFW angiotensinogen (Aogen) mRNA levels (treated: 2.30 +/- 0.37, n = 8 and 2.05 +/- 0.45, n = 7 vs. control: 0.94 +/- 0.12, n = 8 and 0.67 +/- 0.09, n = 7, P < 0.02). Levels of the glucose transporter Glut-1 mRNA were lower in the LVFW of treated fetuses (0.83 +/- 0.23 vs. 1.47 +/- 0.30 in control, P < 0.05, n = 7, 8). The higher the cortisol level, the greater the Aogen mRNA level (RVFW, r = 0.61, P < 0.01, n = 16; LVFW, r = 0.83, P < 0.0003, n = 14). There were no other changes in mRNA levels nor in levels of extracellular kinase, JNK, p38, their phosphorylated forms, and calcineurin. Thus high levels of cortisol such as occur after birth do not affect fetal cardiac myocyte binucleation or number but are associated with higher levels of ventricular Aogen mRNA, lower levels of Glut-1 mRNA, and hypertrophy of LVFW myocytes. These effects could impact on postnatal cardiac development.

Cardiac corticosteroid receptors mediate the enlargement of the ovine fetal heart induced by chronic increases in maternal cortisol

“…The fetal blood pressures from that study were not reported. In a study by Lumbers et al (2005) high dose infusion of cortisol (72 . 1 mg/d for w60 h) increased LV myocyte size and increase cardiac angiotensinogen mRNA, suggesting an induction of hypertrophy.…”

“…Giraud et al (2006) have shown that cortisol chronically infused directly into the coronary artery increased cell cycle activity in myocytes of late gestation sheep fetuses, suggesting a direct induction by cortisol of hyperplastic growth rather than hypertrophic growth. Conversely, it has been demonstrated that large doses of cortisol infused directly into the fetus in late gestation causes left ventricular (LV) hypertrophy along with an increase in fetal arterial pressure and cardiac expression of angiotensinogen mRNA (Lumbers et al 2005). We have shown that maternal cortisol infusion in sheep during late gestation caused an increase in fetal heart size and wall thickness without increasing fetal arterial pressure or cardiac angiotensinogen; we found an increase in the ratio of angiotensin type 2 receptor (AT2 receptor) to AT1 receptor mRNA in the fetal heart, suggesting that the renin-angiotensin system (RAS) may play a key role in the enlargement process.…”

Bigger is not better: cortisol-induced cardiac growth and dysfunction in salmonids

“…is associated with abnormal heart growth and other cardiovascular diseases (Souverein et al, 2004). In mammalian experimental models, glucocorticoids like cortisol directly induce cardiomyocyte hypertrophy in vitro (Whitehurst et al, 1999;Ren et al, 2012) and in vivo (Clark et al, 1982;de Vries et al, 2002;Jensen et al, 2002;Lumbers et al, 2005), indicating a direct role of cortisol in heart remodelling, growth and disease.…”

Cortisol response to stress is associated with myocardial remodeling in salmonid fishes

“…In contrast to mammals, where aldosterone is an important hormone in myocardial remodeling (Funder, 2001;Rocha et al, 2002;Qin et al, 2003), most teleosts, including salmonids, do not produce aldosterone (Bern, 1967;Sangalang and Uthe, 1994), and mineralcorticoid functions are instead mediated by cortisol (Bern and Madsen, 1992;Wendelaar Bonga, 1997). Furthermore, in mammals, glucocorticoids like cortisol directly induce protein synthesis and hypertrophy of cardiomyocytes in vivo and in vitro (Nichols et al, 1984;Lumbers et al, 2005), and plasma cortisol levels have been found to represent an independent risk factor of cardiac events and death (Yamaji et al, 2009). Accordingly, to examine the effect of stress and cortisol on myocardial morphology and function, we examined cardiac structure and gene expression in the hearts of two genetically distinct strains of rainbow trout (Oncorhynchus mykiss Walbaum 1792) that respond to stress with either a high [high responsive (HR)] or low [low responsive (LR)] cortisol production (Pottinger and Carrick, 1999).…”