Chronic cardiac-specific thyrotoxicosis increases myocardial beta-adrenergic responsiveness.
Whereas many cardiac symptoms of thyrotoxicosis resemble those of the hyperadrenergic state, circulating catecholamines are reduced or normal in this condition. To test the hypothesis that the thyrotoxic heart is hypersensitive to catechol-amines, we studied beta-adrenergic signaling in a transgenic (TG) mouse in which the human type 2 iodothyronine deiodinase (D2) gene is expressed in myocardium. Because D2 converts T4 to T3, the active form of thyroid hormone, the D2 TG mouse exhibits mild, chronic thyrotoxicosis that is limited to the myocardium. In the current study, we determined that cAMP accumulation in response to either norepinephrine or forskolin treatment was increased in isolated ventricular myocardiocytes and membrane-enriched fractions prepared from these D2 TG hearts as compared with wild type. This increase in adenylyl cyclase (AC) Vmax could not be explained by changes in AC isoform expression or changes in the long or short forms of stimulatory G-protein Gsalpha, which were approximately 10% decreased in D2 TG membranes. However, Western analysis and ADP-ribosylation studies suggest that the increase in AC Vmax is mediated by a decrease in the expression of inhibitory G proteins (Gialpha-3 and/or Goalpha). These data suggest that cardiac thyrotoxicosis leads to increased beta-adrenergic responsiveness of cardiomyocytes via alterations in the regulatory G-protein elements of the AC membrane complex.
Carvalho-Bianco
Suzy D
SD
Division of Endocrinology, Diabetes and Hypertension, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kim
Brian W
BW
Zhang
Julie X
JX
Harney
John W
JW
Ribeiro
Rogério S
RS
Gereben
Balazs
B
Bianco
Antonio C
AC
Mende
Ulrike
U
Larsen
P Reed
PR
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013971:Thyrotoxicosis / Q000378:metabolism* / Q000503:physiopathology; D000097564:Iodothyronine Deiodinase Type II
D000262:Adenylyl Cyclases; D005576:Colforsin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D007453:Iodide Peroxidase; D007527:Isoenzymes; D009638:Norepinephrine; D011943:Receptors, Adrenergic, beta; D000097564:Iodothyronine Deiodinase Type II; C419510:adenylyl cyclase type V