Abstract
Background Rheumatoid Arthritis (RA) patients show a higher risk of heart failure. The present study investigated possible causes of cardiac dysfunction related to thyroid hormone (TH) signaling in a RA mouse model. Methods A TNF-driven mouse model of RA[TghuTNF (Tg197)] was used. Cardiac function was evaluated by echocardiography. SERCA2a and phospholamban protein levels in left ventricle (LV) tissue, thyroid hormone levels in serum, TH receptors in LV and TH-related kinase signaling pathways were measured. T3 hormone was administered in female Tg197 mice. Results We show LV and atrial dilatation with systolic dysfunction in Tg197 animals, accompanied by downregulated SERCA2a. We suggest an interaction of pro-inflammatory and thyroid hormone signaling indicated by increased p38 MAPK and downregulation of TRβ1 receptor in Tg197 hearts. Interestingly, female Tg197 mice showed a worse cardiac phenotype related to reduced T3 levels and Akt activation. T3 supplementation increased Akt activation, restored SERCA2a expression and improved cardiac function in female Tg197 mice. Conclusions TNF overexpression of Tg197 mice results in cardiac dysfunction via p38 MAPK activation and downregulation of TRβ1. Gender-specific reduction in T3 levels could cause the worse cardiac phenotype observed in female mice, while T3 administration improves cardiac function and calcium handling via modified Akt activation.
Highlights
Chronic Inflammatory Joint diseases, such as Rheumatoid arthritis (RA), Spondyloarthritis and Psoriatic Arthritis are mainly associated with articular inflammation eventually leading to bone erosion and joint damage
We have previously showed that the human Tumor Necrosis Factor Tg197 arthritis mouse model [10], in parallel to its RA pathology, develops TNF-driven valvular heart disease (VHD), which mainly leads to valvular thickening with some degree of stenosis and occasionally insufficiency [11]
Echocardiographic assessment revealed that left ventricular internal diameter at end-diastolic phase (LVEDd) and left ventricular internal diameter at endsystolic phase (LVESd) were significantly increased in both Tg197 males and females compared to WT mice (Table 1)
Summary
Chronic Inflammatory Joint diseases, such as Rheumatoid arthritis (RA), Spondyloarthritis and Psoriatic Arthritis are mainly associated with articular inflammation eventually leading to bone erosion and joint damage. More mechanistic studies are needed to elucidate the underlying mechanisms Unravelling these mechanisms would allow a better understanding of the pathophysiology of HF in RA patients, facilitating the development of new and more specific treatments. In this regard, we have previously showed that the human Tumor Necrosis Factor (huTNF) Tg197 arthritis mouse model [10], in parallel to its RA pathology, develops TNF-driven VHD, which mainly leads to valvular thickening with some degree of stenosis and occasionally insufficiency [11]. The present study investigated possible causes of cardiac dysfunction related to thyroid hormone (TH).
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