Changes in cardiac TRPM6 and TRPM7 expression during late gestation and transition to extra-uterine life in preterm and term piglets

Abstract

Cardiovascular compromise in the first days of life is common in preterm infants. Current treatments to support cardiovascular function include volume expansion with crystalloids and then administration of adrenergic inotropes. However, neither treatment is effective at improving neurodevelopmental outcomes, and may even be detrimental, so there is a critical need to identify new treatment targets. One factor that may contribute to cardiovascular compromise is functional immaturity of the preterm heart, as indicated by limited myocardial contractility and low cardiac output. This functional immaturity may be related to Ca2+ handling, which is critical to cardiac function and is likely to be immature in the preterm myocardium. Therefore, improved Ca2+ handling may provide an alternative treatment target. Two transmembrane cation channels, TRPM6 and TRPM7, serve as novel candidates in regulating intracellular cardiac calcium in the neonatal period. The aim of this study was to determine; a) the ontogeny of TRPM6 and TRPM7 mRNA expression in neonatal piglet hearts in late gestation, b) the effect of maternal glucocorticoids on the expression of TRPM6 and TRPM7 in preterm piglets, and c) the effect of transition to extrauterine life on TRPM6 and TRPM7 expression in preterm and term piglets.The mRNA expression of TRPM6 and TRPM7 was quantified in both the left and right ventricle of piglet hearts across late gestation (91d, 97d, 100d, 113d; full term 115d) using quantitative real-time PCR. Additionally, expression of these channels 6 hours after birth was quantified at 97d and 113d. Given that a majority of preterm infants are exposed to maternal corticosteroids, their effect on expression of TRPM6 and TRPM7 in preterm piglets delivered at 91d and 97d was assessed both at birth and at 6h of postnatal life.Expression of TRPM6 and TRPM7 in the left ventricle was similar throughout late gestation. Expression of TRPM7 was lower in male piglets compared to females. The effect of maternal glucocorticoids on expression of TRPM6 and TRPM7 varied with gestational age, postnatal age and ventricle. There was a decrease in expression of TRPM7 in the left ventricle of piglets born at 91d who had maternal glucocorticoid exposure, but no change in expression at birth following exposure in those born at 97d. Maternal glucocorticoids led to increased TRPM7 expression in the right ventricle of 97d piglets at 6h of postnatal life. In the left ventricle, expression of TRPM7 was increased after 6h of postnatal life in term piglets only. In the right ventricle, expression of both TRPM6 and TRPM7 was increased after 6h of extrauterine life in term piglets. In the right ventricle, expression of TRPM6 and TRPM7 were bimodally distributed at some gestational ages. Expression of TRPM6 and TRPM7 were highly correlated in both left and right ventricles.In conclusion, higher expression of TRPM7 in female preterm piglets may contribute to improved myocardial Ca2+ handling and therefore account for lower morbidity risk compared to their male counterparts. The changes in TRPM6 and TRPM7 expression at birth following maternal glucocorticoid exposure do not seem to account for the beneficial effect of maternal glucocorticoids on the cardiovascular system in preterm piglets. Finally, transient upregulation of TRPM7 in early postnatal life could be the mature response to birth that is missing in steroid naive preterm neonates but is present in preterm neonates exposed to maternal glucocorticoids. These results suggest that TRPM7 could serve as a novel target to help improve cardiac function in preterm neonates.