Differential regulation of the myosin heavy chain genes α and β in rat atria and ventricles:: Role of antisense RNA

Background: The myosin heavy chain (MHC) genes are regulated by triiodothyronine (T-3) in a reciprocal and chamber-specific manner. To further our understanding of the potential mechanisms involved, we determined the T-3 responsiveness of the MHC genes, alpha and beta, and the beta-MHC antisense (AS) gene in the rat ventricles and atria. Methods: Hypothyroid rats were administered a single physiologic (1 mu g) or pharmacologic (20 mu g) dose of T-3, and sequential measurements of beta-MHC hn- and AS RNA and alpha-MHC heterogeneous nuclear RNA from rat ventricular and atrial myocardium were performed with reverse transcription PCR. Results: We have demonstrated that T-3 treatment increases the myocyte content of an AS beta-MHC RNA in atria and ventricles that includes sequences complementary to both the first 5' and last 3' introns of the beta-MHC sense transcript. In the hypothyroid rat ventricle, beta-MHC sense RNA expression is maximal, while in the euthyroid rat ventricle, beta-MHC AS RNA is maximal. beta-MHC AS expression increased by 52 +/- 9.8% at the peak, 24 hours after injection of a physiologic dose of T-3 (1 mu g/animal), while beta-MHC sense RNA decreased by 41 +/- 2.2% at 36 hours, the nadir. In hypothyroid atria, beta-MHC AS RNA was induced by threefold within 6 hours of administration of 1 mu g T-3, demonstrating that in the atria, beta-MHC AS expression is regulated by T-3, while alpha-MHC expression is not. Conclusions: In the hypothyroid rat heart ventricle, beta-MHC AS RNA expression increases in response to T-3 similar to that of alpha-MHC. Simultaneous measures of beta-MHC sense RNA are decreased, suggesting a possible mechanism for AS to regulate sense expression. In atria, while alpha-MHC is not influenced by thyroid state, beta-MHC sense and AS RNA were simultaneously and inversely altered in response to T-3. This confirms a close positive relationship between T-3 and beta-MHC AS RNA in both the atria and ventricles, while demonstrating for the first time that alpha-and beta-MHC expression is not coupled in the atria.