PSIX-8 Increased Expression of ST6GAL1 and Vegfa Mediate the Inflammatory Signaling Pathway in Feline Hyperthyroidism
Authors: Tavener Selena K , Hollar Regina L , Panickar Kiran S 
Published: November 2023

Abstract
Hyperthyroidism in cats is characterized by increased production of thyroid hormones including thyroxine (T4) and triiodothyronine (T3) and decreased levels of thyroid stimulating hormone (TSH). Older cats are at greater risk of developing hyperthyroidism. The common clinical signs include increased appetite, body weight loss, increased thirst and urination, periodic vomiting, and rapid heart rate. While the etiology of this disease in cats is not clear, it is likely multi-factorial and environmental, nutritional, and immunological factors have been implicated. We assessed the levels of inflammatory markers in thyroid tissue from cats housed in the Hill’s colony, at the natural end-of-life after living full lives. Cats that were diagnosed as having hyperthyroidism by a veterinarian (n = 10, 12.1-18.9 yr) had greater circulating fT4 when compared with controls. Control cats showed no signs of hyperthyroidism (n = 10, 10.9 to 18.6 yr). Histopathological analysis of hematoxylin and eosin-stained thyroid sections showed an increase in follicular cells as well as evidence of colloid reabsorption in cats with hyperthyroid when compared with controls. RNA was extracted from samples collected from cats and gene expression was investigated using the NanoString nCounter platform. Analysis was performed using the nSolver software. There was a significant increase in ST6GAL1 sialyltransferase when compared with controls (1.22 fold; P &lt; 0.05). ST6GAL1 is an enzyme that can post-translationally modify glycoproteins by adding α2-6-linked sialic acids to them. ST6GAL1 can also regulate the NFκB inflammatory signaling pathway by promoting its sustained activation that can potentially lead to inflammation. In the present study we also saw a decrease in NFκB1/p105 (-1.14, ns), a protein that is processed to produce p50, an NFκB binding protein, but a small increase in NFκB2/p100 (1.06, ns), a protein that is processed to produce p52 of the NFκB signaling pathway in hyperthyroid cats when compared with controls. NFκB1 is a transcriptional repressor and a decline in its expression has been reported to contribute to increased inflammation. Further, an increase in NFκB2 may lead to increased activation of NFκB signaling as p52/RelB dimer is a transcriptional activator of NFκB signaling. There was also an increase in VEGFA in hyperthyroid when compared with controls (1.79 fold; P &lt; 0.05). VEGF is an angiogenesis factor and increasing evidence indicates that angiogenesis sustains inflammation. VEGF is produced by endothelial cells, macrophages and activated T-cells and is also a potent chemoattractant for monocytes. While VEGF induces several pro-inflammatory genes including IL-8 and MCP-1, both were downregulated in hyperthyroid in the present study, indicating that the effects of VEGF were likely not mediated by pro-inflammatory IL-8 or MCP-1 in feline hyperthyroidism. Our data indicate that the etiology of hyperthyroidism involves multiple inflammatory signaling pathways and these may represent important therapeutic targets for reducing inflammation in feline hyperthyroidism.