MitoQ ameliorates diabetic cardiomyopathy by inhibiting mtROS-TXNIP-NLRP3 pathway activation in mice

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, characterized by myocardial dysfunction independent of coronary artery disease or hypertension, for which effective treatments remain limited. A key pathogenic factor in DCM is mitochondrial dysfunction, leading to excessive production of mitochondrial reactive oxygen species (mtROS). This oxidative stress can trigger inflammatory pathways, particularly the NLRP3 inflammasome, which contributes to myocardial injury and fibrosis. Understanding and targeting this mtROS-driven inflammatory cascade is crucial for developing novel DCM therapies.

Researchers established in vivo DCM models in mice using a high-fat diet combined with streptozotocin injection, and in vitro models by exposing AC16 cardiomyocytes to high glucose. Mice were treated with MitoQ (dose not specified in abstract). Key protein expression levels of TXNIP, NLRP3, and Caspase-1 were analyzed in cardiac tissue and cardiomyocytes using immunohistochemistry (IHC) and western blotting. mtROS fluorescence staining assessed ROS generation, while Co-IP experiments confirmed TXNIP-NLRP3 interaction and inflammasome activation. TXNIP knockdown experiments further elucidated the pathway's role.

Diabetic mice exhibited significantly increased oxidative stress, enhanced mtROS accumulation, and activation of the TXNIP/NLRP3 inflammasome pathway, leading to myocardial fibrosis and impaired cardiac function. In high-glucose-stimulated AC16 cells, there was a clear promotion of TXNIP dissociation from TRX, an enhanced TXNIP-NLRP3 interaction, and increased expression of downstream pyroptosis-related proteins, including NT-gasdermin D (GSDMD), Caspase-1, and cleaved interleukin-1β (IL-1β).