The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.

Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin‐(1‐7) is able to block T3‐induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin‐(1‐7) effects. Angiotensin‐(1‐7) treatment increased nuclear FOXO3 levels and reduced p‐FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin‐(1‐7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor‐κB (NF‐κB) were observed after angiotensin‐(1‐7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin‐(1‐7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF‐κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin‐(1‐7), which may contribute to future therapeutic targets.

Cardiovascular diseases are the most common cause of death worldwide and thyroid diseases are frequently associated with cardiac function impairment. Hypothyroidism is related to dilation of the ventricles, fibrosis and consequent reduction in cardiac contractility, as well as an increased risk of heart failure. Recent studies have demonstrated the participation of the NLRP3 inflammasome, an important mechanism of the innate immune response, in cardiovascular diseases, such as myocardial infarction and atherosclerosis. There is evidence in the literature that hypothyroidism is accompanied by increased levels of cytokines and oxidative stress, processes that can activate the inflammasome. The aim of the present study is to evaluate the role of the NLRP3 inflammasome in the heart of hypothyroid mice. For this, Wild Type (WT) mice treated with methimazole (0.05% added to drinking water for 12 weeks) were used (N=4-6). All protocols used in this study were approved by the Animal Ethics Committee of the Institute of Biomedical Sciences (9768300119). Thyroid hormones were quantified by bead-based immunoassay Luminex to confirm the efficacy of experimental model. Fibrosis was analyzed by histology, using picrosirius red staining. Cardiac function was evaluated in mice by plethysmography and in isolated hearts after ischemia/reperfusion by the Langendorff method. Protein expression of NLRP3 inflammasome components was evaluated by Western Blotting. Data were analyzed by one-way ANOVA or Student's t test. Results are presented as mean ± standard error of the mean, and p<0.05 was considered statistically significant. Increased TSH levels (control=92±33, hypo=369±62 (pg/ml)) and reduced T4 (control=1.16±0.38, hypo=0.03±0.01 (ng/ml)) confirmed the hypothyroid status of mice. The heart weight/tibial length ratio and fibrosis were not altered by hypothyroidism. Heart rate was reduced in hypothyroid mice (control=663±27, hypo=541±28 (bpm)). No differences were detected in the cardiac function parameters after Ischemia-Reperfusion injury: left ventricular developed pressure (LVDP), maximum (dP/dtmax) or minimum first derivative (dP/dtmin). Concerning to inflammasome, NLRP3 expression was reduced (control=100±16, hypo=29±14 (%)) and pro-caspase 1 increased (control=100±17, hypo=259±43 (%)) in hypothyroid hearts. These preliminary results showed characterization data for experimental hypothyroidism and that this condition can modulate inflammasome expression. Additional experiments are underway to confirm the role of the NLRP3 inflammasome on cardiac function in hypothyroid mice. FAPESP (grants nº 2021/06151-7 and 2019/17031-2) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.