Differential regulation of the myosin heavy chain genes alpha and beta in rat atria and ventricles: role of antisense RNA.
BACKGROUND
The myosin heavy chain (MHC) genes are regulated by triiodothyronine (T3) in a reciprocal and chamber-specific manner. To further our understanding of the potential mechanisms involved, we determined the T3 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 microg) or pharmacologic (20 microg) dose of T3, 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 T3 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 T3 (1 microg/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 microg T3, demonstrating that in the atria, beta-MHC AS expression is regulated by T3, while alpha-MHC expression is not.


CONCLUSIONS
In the hypothyroid rat heart ventricle, beta-MHC AS RNA expression increases in response to T3 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 T3. This confirms a close positive relationship between T3 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.
Danzi
Sara
S
Feinstein Institute for Medical Research and the Department of Medicine, North Shore University Hospital, Manhasset, New York 11030, USA.
Klein
Steven
S
Klein
Irwin
I
D000818:Animals; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood / Q000494:pharmacology; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism*
D016372:RNA, Antisense; D014284:Triiodothyronine; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D013974:Thyroxine