Cardiac hypertrophy that affects hyperthyroidism occurs independently of the NLRP3 inflammasome.

Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1ß production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8-12 weeks, by triiodothyronine (7 µg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice.

Impact of hyperthyroidism on cardiac hypertrophy.

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and it is critically involved in maintenance of cardiac homeostasis. This process enables organism adaptation to changes of 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 physiologic response or non-adaptive pathologic response. 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 heart 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 signaling pathways associated. In addition to classical crosstalk with the Sympathetic Nervous System (SNS), emerging work points to the new endocrine interaction between TH and 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 that target key mechanisms responsible for TH-induced cardiac hypertrophy.