TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway.

Abstract

Diabetic cardiomyopathy (DCM) is identified as a progressive disease that may lead to irreparable heart failure. Toll-like receptor (TLR) signaling is believed to be implicated in the pathogenesis of DCM. This study intended to explore the potential impact of Toll-like receptor 4 (TLR4) on DCM in vitro and in vivo. Streptozotocin and HG medium were utilized to induce diabetes in animal and cell models, respectively. Selective TLR4 inhibitor TAK-242 and calcium/calmodulin-dependent protein kinase-II (CaMKII) inhibitor KN-93 were employed to explore the involvement of TLR4/CaMKII in DCM. TLR4 expression was increased in DCM hearts, while inhibition of TLR4 activation by TAK-242 improved cardiac function, attenuated heart hypertrophy, and fibrosis, as well as reduced oxidative stress and proinflammatory cytokine levels in rats, which were confirmed by Doppler echocardiography, hematoxylin and eosin staining, and Masson Trichome staining and specific enzyme-linked immunosorbent assay kits. Besides, the expression of hypertrophy-related molecules and oxidative stress damage were also inhibited by TAK-242. Furthermore, TAK-242 treatment reduced CaMKII phosphorylation accompanied by decreased expression of NOD-like pyrin domain-containing protein 3, gasdermin D (GSDMD), The N-terminal domain of Gasdermin D (GSDMD-N), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and Caspase-1 both in vivo and in vitro. Similar positive impacts on HG-induced pyroptosis were also observed with KN-93 treatment, and this was achieved without affecting TLR4 expression. Collectively, our work suggested that TAK-242 demonstrated substantial benefits against DCM both in vivo and in vitro, potentially attributed to the suppression of the TLR4-mediated CaMKII/NLRP3 pathway activity.