Regulation of Na/K-ATPase Gene Expression by Thyroid Hormone and Hyperkalemia in the Heart

Abstract

Hypothermic hyperkalemic circulatory arrest has been widely used for myocardial protection during heart surgery. Recent data showed that administration of triiodo-L-thyronine (T₃) postoperatively enhanced ventricular function. The effect of hyperkalemic arrest in conjunction with thyroid hormone on the plasma membrane enzyme sodium/potassium-adenosine triphosphatase (Na/K-ATPase), was determined in cultured neonatal rat atrial and ventricular myocytes. Exposure of ventricular myocytes to hyperkalemic medium (50 mM KCl) in the absence of T₃ increased expression of the Na/K-ATPase catalytic subunit mRNAs, α₁ and α₃ isoforms, by 1.9- and 1.5-fold, respectively (p < 0.01), which were accompanied by similar increases (1.4- and 1.8-fold) in protein content. Addition of T₃ to the hyperkalemic cultures attenuated these increases in Na/K-ATPase mRNA isoforms to levels of expression observed in cells treated with T₃ (10^-8 M) alone. Similarly, expression of the α₁ mRNA isoform in atrial myocytes was increased (p < 0.05) by hyperkalemic conditions, and T₃ treatment attenuated this effect. In contrast, although expression of the Na/K-ATPase β₁ mRNA in both atrial and ventricular myocytes was significantly increased by hyperkalemia, addition of T₃ did not prevent the hyperkalemic response, and in atrial myocytes T₃ significantly increased β₁ mRNA expression 1.8-fold. These results show that expression of cardiac Na/K-ATPase is regulated by T₃ and hyperkalemia in an isoform and chamber specific manner, and suggest that use of hyperkalemic cardioplegia during heart surgery may alter plasma membrane ion function.