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Molecular Medicine

, Volume 20, Issue 1, pp 302–312 | Cite as

Low-Dose T3 Replacement Restores Depressed Cardiac T3 Levels, Preserves Coronary Microvasculature and Attenuates Cardiac Dysfunction in Experimental Diabetes Mellitus

  • Nathan Y. Weltman
  • Kaie Ojamaa
  • Evelyn H. Schlenker
  • Yue-Feng Chen
  • Riccardo Zucchi
  • Alessandro Saba
  • Daria Colligiani
  • Viswanathan Rajagopalan
  • Christine J. Pol
  • A. Martin Gerdes
Research Article

Abstract

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 µg/mL T3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T3 and T4: 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T3 replacement largely restored cardiac tissue TH levels (T3 and T4: 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Notes

Acknowledgments

We would like to thank Alice O’Connor (New York Institute of Technology College of Osteopathic Medicine [NYIT-COM] Histology Core) for her assistance with slide processing and histological staining, Jie Li (University of South Dakota) for her assistant with LV echocardiography measurements, and Alan Joy (NYIT-COM) for his help with LV fibrosis quantification. We would also like to thank Timothy Gant and Kate Dudek for their generosity in providing the DIO3 sequences. MHC antibodies (S58 and F59) were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and maintained by The University of Iowa, Department of Biology, Iowa City, IA. This project was supported by Grant Numbers RO1HL093160-01A1 and RO1HL103671 (AM Gerdes) from the National Heart, Lung, and Blood Institute (NHLBI). This research was also supported by an American Diabetes Association (ADA) Clinical Scientist Training Award 7-10-CST-01 (NY Weltman and AM Gerdes). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH), the NHLBI or the ADA. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Supplementary material

10020_2014_2001302_MOESM1_ESM.pdf (4.4 mb)
Supplementary material, approximately 4.36 MB.

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Authors and Affiliations

  • Nathan Y. Weltman
    • 1
  • Kaie Ojamaa
    • 2
  • Evelyn H. Schlenker
    • 1
  • Yue-Feng Chen
    • 4
  • Riccardo Zucchi
    • 3
  • Alessandro Saba
    • 3
  • Daria Colligiani
    • 3
  • Viswanathan Rajagopalan
    • 4
  • Christine J. Pol
    • 4
  • A. Martin Gerdes
    • 4
  1. 1.Department of Basic Biomedical Sciences, Sanford School of MedicineUniversity of South DakotaVermillionUSA
  2. 2.Center for Heart and Lung Research, North Shore-LIJ Health SystemThe Feinstein Institute for Medical ResearchManhassetUSA
  3. 3.Dipartimento di Scienze dell’Uomo e dell’AmbienteUniversity of PisaPisaItaly
  4. 4.Department of Biomedical SciencesNew York Institute of Technology College of Osteopathic Medicine (NYIT-COM)Old WestburyUSA

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