Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Butanta, Sao Paulo, 05508-000, Brazil.
Department of Cardiopneumology, Heart Institute, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
Pflugers Arch. 2024 Jul;476(7):1065-1075. doi: 10.1007/s00424-024-02965-6. Epub 2024 Apr 29.
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-1β 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.
心肌肥厚（CH）是维持心脏功能的一种适应性反应；然而，持续的应激反应会导致收缩功能障碍和心力衰竭。尽管炎症参与了这些过程，但控制心脏炎症和肥厚的机制仍需要阐明。NLRP3 炎性小体是一种细胞溶质多蛋白复合物，介导 IL-1β 的产生。NLRP3 的启动步骤对于增加其组成部分的表达至关重要，并且发生在 NF-κB 激活之后。甲状腺功能亢进会引发 CH，进而发展为适应性不良的 CH，甚至心力衰竭。我们在之前的研究中表明，甲状腺激素（TH）诱导的 CH 与 S100A8 的上调有关，导致 NF-κB 激活。因此，我们旨在研究 NLRP3 炎性小体是否参与 TH 诱导的 CH 及其在 CH 病理生理学中的潜在作用。通过腹腔注射三碘甲状腺原氨酸（7μg/100g BW），每天一次，连续 14 天，在 8-12 周龄的 NLRP3 敲除（NLRP3-KO）、Caspase-1-KO 和野生型（WT）雄性 C57Bl/6J 小鼠中诱导甲状腺功能亢进。形态学和心脏功能分析以及分子检测首次表明，TH 诱导的 CH 伴随着心脏中 NLRP3 表达的降低，并且这种情况独立于 NLRP3 炎性小体和 caspase 1 相关途径发生。然而，NLRP3 对于维持基础心脏功能很重要，因为与 WT 小鼠相比，NLRP3-KO 小鼠的舒张功能受损，心率、射血分数和缩短分数降低。
