Type 2 iodothyronin deiodinase transgene expression in the mouse heart causes cardiac-specific thyrotoxicosis.
Type 2 iodothyronine deiodinase (D(2)) catalyzes intracellular 3, 5, 3' triiodothyronine (T(3)) production from thyroxine (T(4)), and its messenger RNA mRNA is highly expressed in human, but not rodent, myocardium. The goal of this study was to identify the effects of D(2) expression in the mouse myocardium on cardiac function and gene expression. We prepared transgenic (TG) mice in which human D(2) expression was driven by the alpha-MHC promoter. Despite high myocardial D(2) activity, myocardial T(3) was, at most, minimally increased in TG myocardium. Although, plasma T(3) and T(4), growth rate as well as the heart weight was not affected by TG expression, there was a significant increase in heart rate of the isolated perfused hearts, from 284 +/-12 to 350 +/- 7 beats/min. This was accompanied by an increase in pacemaker channel (HCN2) but not alpha-MHC or SERCA II messenger RNA levels. Biochemical studies and (31)P-NMR spectroscopy showed significantly lower levels of phosphocreatine and creatine in TG hearts. These results suggest that even mild chronic myocardial thyrotoxicosis, such as may occur in human hyperthyroidism, can cause tachycardia and associated changes in high energy phosphate compounds independent of an increase in SERCA II and alpha-MHC.
Pachucki
J
J
Thyroid Division, Brigham and Women's Hospital, Harvard Institute of Medicine, Boston, Massachusetts 02115, USA.
Hopkins
J
J
Peeters
R
R
Tu
H
H
Carvalho
S D
SD
Kaulbach
H
H
Abel
E D
ED
Wondisford
F E
FE
Ingwall
J S
JS
Larsen
P R
PR
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000235:genetics; D003402:Creatine Kinase / Q000378:metabolism; D004734:Energy Metabolism; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D009929:Organ Size; D015221:Potassium Channels; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013971:Thyrotoxicosis / Q000235:genetics* / Q000503:physiopathology*; D013974:Thyroxine / Q000097:blood / Q000378:metabolism; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000097:blood
D000227:Adenine Nucleotides; C578710:HCN2 protein, human; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D007527:Isoenzymes; D009124:Muscle Proteins; D015221:Potassium Channels; D012333:RNA, Messenger; D014284:Triiodothyronine; D007453:Iodide Peroxidase; D003402:Creatine Kinase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D013974:Thyroxine