Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan.
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, Japan.
Biochem Pharmacol. 2023 Jun;212:115547. doi: 10.1016/j.bcp.2023.115547. Epub 2023 Apr 11.
The NLR family pyrin domain containing 3 (NLRP3) inflammasome matures interleukin (IL)-1β and induces inflammation. The molecular chaperone heat shock protein 90 (Hsp90) is known to regulate the formation of the NLRP3 inflammasome. However, the pathophysiological role of Hsp90 in the activation of the NLRP3 inflammasome in the failing heart is unclear. In the present study, we examined the pathophysiological role of Hsp90 in IL-1β activation via inflammasomes using rats with heart failure following myocardial infarction in vivo and neonatal rat ventricular myocytes (NRVMs) in vitro. In the failing hearts, immunostained images showed an increase in NLRP3-positive spots. Increases in cleaved caspase-1 and mature IL-1β levels were also observed. In contrast, treatment of the animals with an Hsp90 inhibitor reversed the increases in these values. In in vitro experiments, the activation of NLRP3 inflammasomes and the increase in mature IL-1β induced by exposure of NRVMs to nigericin were attenuated by treatment with the Hsp90 inhibitor. Furthermore, coimmunoprecipitation assays indicated that the administration of an Hsp90 inhibitor to NRVMs attenuated the interaction between Hsp90 and its cochaperone SGT1. Our findings suggest that Hsp90 plays an important role in the regulation of NLRP3 inflammasome formation during the development of chronic heart failure after myocardial infarction in rats.
NLR 家族包含 pyrin 结构域的 3（NLRP3）炎性小体成熟白细胞介素（IL）-1β并诱导炎症。热休克蛋白 90（Hsp90）作为分子伴侣，已知其可调节 NLRP3 炎性小体的形成。然而，Hsp90 在衰竭心脏中 NLRP3 炎性小体激活中的病理生理作用尚不清楚。在本研究中，我们使用体内心肌梗死后心力衰竭大鼠和体外新生大鼠心室肌细胞（NRVMs）研究了 Hsp90 在炎性小体介导的 IL-1β 激活中的病理生理作用。在衰竭的心脏中，免疫染色图像显示 NLRP3 阳性斑点增加。还观察到裂解的 caspase-1 和成熟的 IL-1β 水平增加。相反，用 Hsp90 抑制剂处理动物可逆转这些值的增加。在体外实验中，用 Nigericin 处理 NRVMs 可激活 NLRP3 炎性小体并增加成熟的 IL-1β，用 Hsp90 抑制剂处理可减弱这一作用。此外，共免疫沉淀实验表明，向 NRVMs 中给予 Hsp90 抑制剂可减弱 Hsp90 与其共伴侣 SGT1 之间的相互作用。我们的研究结果表明，Hsp90 在大鼠心肌梗死后慢性心力衰竭发展过程中 NLRP3 炎性小体形成的调节中起重要作用。
