Thyroid hormone resistance in the heart: role of the thyroid hormone receptor beta isoform.
Several cardiac genes possess thyroid hormone (TH) response elements regulated by TH receptors. Mutation in TR-beta gene causes the human syndrome of resistance to TH, which is characterized by elevated serum concentration of T(4) and T(3) and variable degrees of insensitivity to TH. It is unclear, however, whether a mutant TR-beta could function as a dominant negative in the heart when expressed from the endogenous locus. A well-described resistance to TH (Delta337T) was either introduced into germline of mice (KI-mut) or expressed as a transgene in the heart using a cardiac-specific promoter (KS-mut). Mice were studied at baseline, after 5-propyl-2-thiouracil (PTU) or after PTU and T(3) treatment (PTU + T(3)). PTU + T(3) treatment significantly increased left ventricular mass in all groups compared with baseline measurements, although the increase in left ventricular mass was significantly less in KI-mut animals. Baseline heart rates (HRs) were similar in wild-type (WT) and KI-mut but were lower in KS-mut animals. After TH deprivation (PTU), HR decreased in WT and KI-mut animals; similarly, HR increased in WT and KI-mut after PTU + T(3). In contrast, HR in KS-mut animals did not change after either treatment. Except for cardiac hypertrophy, the presence of a germline TR-beta mutation had surprisingly little effect on cardiac function.
Ortiga-Carvalho
Tania M
TM
Department of Medicine, Pritzker School of the Medicine, The University of Chicago, Illinois 60637, USA.
Hashimoto
Koshi
K
Pazos-Moura
Carmen C
CC
Geenen
David
D
Cohen
Ronald
R
Lang
Roberto M
RM
Wondisford
Fredric E
FE
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004452:Echocardiography; D015870:Gene Expression; D018095:Germ-Line Mutation; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011441:Propylthiouracil / Q000494:pharmacology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D018382:Thyroid Hormone Resistance Syndrome / Q000000981:diagnostic imaging / Q000503:physiopathology*; D013963:Thyroid Hormones / Q000097:blood; D014284:Triiodothyronine / Q000494:pharmacology
D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D014284:Triiodothyronine; D011441:Propylthiouracil