Low-Dose T3 Replacement Restores Depressed Cardiac T3 Levels, Preserves Coronary Microvasculature and Attenuates Cardiac Dysfunction in Experimental Diabetes Mellitus
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.
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.
- 4.Yoon Y, et al. (2005) Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy — Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation. 111:2073–85.CrossRefPubMedGoogle Scholar
- 12.McQuade C, Skugor M, Brennan D, Hoar B, Stevenson C, Hoogwerf B. (2011) Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a preCIS database study. Thyroid. 21:837–43.CrossRefPubMedGoogle Scholar
- 33.Institute of Laboratory Animal Resources (U.S.), Committee on Care and Use of Laboratory Animals. (1985) Guide for the Care and Use of Laboratory Animals. Rev. 1985. Bethesda (MD): NIH. 83 pp. (NIH publication; no. 85–23).Google Scholar
- 61.Liu Y, Wang D, Redetzke R, Sherer BA, Gerdes AM. (2009) Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function. Am. J. Physiol. Heart Circ. Physiol. 296:H1551–7.CrossRefPubMedPubMedCentralGoogle Scholar
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