title: Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice.
abstract: Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction.
authors.affiliation: University of Massachusetts Medical School, Program in Molecular Medicine, 368 Plantation Street, Sherman Center, AS9.1041, Worcester, Massachusetts 01605. jason.kim@umassmed.edu.
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: Brian W
authors.initials: BW
authors.lastname: Kim
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Tim
authors.initials: T
authors.lastname: Yu
authors.forename: Wagner
authors.initials: W
authors.lastname: Seixas Da Silva
authors.forename: Randall H
authors.initials: RH
authors.lastname: Friedline
authors.forename: Suzy D
authors.initials: SD
authors.lastname: Bianco
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Seslar
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Charles I
authors.initials: CI
authors.lastname: Berul
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: P Reed
authors.initials: PR
authors.lastname: Larsen
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D004317:Doxorubicin / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007333:Insulin Resistance; D007453:Iodide Peroxidase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014284:Triiodothyronine / Q000378:metabolism; D014463:Ultrasonography; D018754:Ventricular Dysfunction / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D055372:AMP-Activated Protein Kinases; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005947:Glucose; D051272:Glucose Transporter Type 1; D007453:Iodide Peroxidase; D051057:Proto-Oncogene Proteins c-akt; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C495679:Slc2a1 protein, rat; C494920:Akt1 protein, rat