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Background <p>Uncoupling protein 2 (UCP2) is implicated in cardiomyocyte apoptosis and diabetes, yet its role in diabetic cardiomyopathy (DCM) remains unclear. This study aimed to elucidate the mechanisms by which UCP2 influences DCM pathogenesis.</p> Methods <p>We examined UCP2 expression in DCM mice and assessed cardiac function via echocardiography. Myocardial fibrosis and hypertrophy were evaluated using Masson trichrome staining and wheat germ agglutinin (WGA) staining. The mitochondrial-targeted reactive oxygen species (ROS) scavenger mito-TEMPO was used to investigate the role of ROS. Mechanistic studies were conducted in H9C2 cells, focusing on ROS production, mitochondrial membrane potential, and the thioredoxin-interacting protein (TXNIP)/NLR family pyrin domain containing 3 (NLRP3)/gasdermin D (GSDMD) pathway.</p> Results <p>UCP2 was upregulated in DCM mice hearts, and its inhibition worsened cardiac function, increased myocardial fibrosis, and aggravated cardiomyocyte hypertrophy. UCP2 knockdown in H9C2 cells elevated ROS levels, reduced mitochondrial membrane potential, and activated the TXNIP/NLRP3/GSDMD pathway, leading to pyroptosis. Mito-TEMPO partially reversed these effects by reducing ROS and suppressing NLRP3 and pyroptosis-related proteins.</p> Conclusions <p>UCP2 inhibition exacerbates DCM by inducing NLRP3- and GSDMD-mediated pyroptosis via the ROS/TXNIP axis. These findings offer new insights into DCM pathogenesis and potential therapeutic targets.</p>

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UCP2 inhibition exaggerates diabetic cardiomyopathy by facilitating the activation of NLRP3 and pyroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月16日

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  • Lixia Zhang,
  • Chenchen Ai,
  • Changlei Guo,
  • Shuqi Li,
  • Jinglei Niu,
  • Xiaoxue Meng,
  • Zheng Zhang

摘要

Background

Uncoupling protein 2 (UCP2) is implicated in cardiomyocyte apoptosis and diabetes, yet its role in diabetic cardiomyopathy (DCM) remains unclear. This study aimed to elucidate the mechanisms by which UCP2 influences DCM pathogenesis.

Methods

We examined UCP2 expression in DCM mice and assessed cardiac function via echocardiography. Myocardial fibrosis and hypertrophy were evaluated using Masson trichrome staining and wheat germ agglutinin (WGA) staining. The mitochondrial-targeted reactive oxygen species (ROS) scavenger mito-TEMPO was used to investigate the role of ROS. Mechanistic studies were conducted in H9C2 cells, focusing on ROS production, mitochondrial membrane potential, and the thioredoxin-interacting protein (TXNIP)/NLR family pyrin domain containing 3 (NLRP3)/gasdermin D (GSDMD) pathway.

Results

UCP2 was upregulated in DCM mice hearts, and its inhibition worsened cardiac function, increased myocardial fibrosis, and aggravated cardiomyocyte hypertrophy. UCP2 knockdown in H9C2 cells elevated ROS levels, reduced mitochondrial membrane potential, and activated the TXNIP/NLRP3/GSDMD pathway, leading to pyroptosis. Mito-TEMPO partially reversed these effects by reducing ROS and suppressing NLRP3 and pyroptosis-related proteins.

Conclusions

UCP2 inhibition exacerbates DCM by inducing NLRP3- and GSDMD-mediated pyroptosis via the ROS/TXNIP axis. These findings offer new insights into DCM pathogenesis and potential therapeutic targets.