Thyroid hormone regulates Na+-Ca2+ exchanger expression during postnatal maturation and in adult rabbit ventricular myocardium

Abstract

Expression of the cardiac Na⁺-Ca²⁺ exchanger (NCX) is high at birth and declines rapidly to adult levels by approximately 21 days in rabbits. The aim was to evaluate the role of thyroid hormone in regulating cardiac NCX expression. Adult New Zealand White rabbits were made hypothyroid by treatment with propylthiouracil or hyperthyroid by administration of l-thyroxine. Hypothyroidism was induced in immature rabbits by exposure to propylthiouracil from gestational day 25 through the first 21 days after birth. NCX steady-state mRNA levels were quantitated using Northern slot blots with poly(A⁺) RNA isolated from ventricular myocardium of treated and age-matched euthyroid animals. As a control, steady-state levels of cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) were measured in each group. Thyroid status was confirmed with serum T₄, ventricular weight and body weight measurements. Immunoreactive NCX protein levels were assessed using Western blots. Compared with euthyroid controls, NCX steady-state mRNA levels increased to 189 ± 20% in hypothyroid adults and decreased to 55 15% in hyperthyroid adults. Opposite effects were observed for SERCA2a expression (58 + 7% in hypothyroidism and 130 +- 15% in hyperthyroidism). In hypothyroid 21-day-old rabbits, NCX steady-state mRNA levels were elevated to 205 ± 30% of age-matched euthyroid controls. SERCA2a levels were unaffected in the immature animals, possibly due to inability to reduce thyroid levels sufficiently to affect SERCA2a expression in this model. Changes in NCX mRNA levels produced comparable changes in immunoreactive NCX protein levels. Thyroid hormone reciprocally regulates NCX and SERCA2a expression in the ventricles of adult rabbits. Hypothyroidism resulted in sustained high levels of NCX expression in 21-day-old rabbits. These results suggest that the postnatal thyroid hormone surge is important for the normal down-regulation of cardiac NCX expression during the first 3 weeks after birth in developing rabbits.