Alda-1 functions as an agonist of aldehyde dehydrogenase (ALDH2) within the mitochondria, contributing to the preservation of mitochondrial structure and function. This study aimed to determine whether Alda-1 inhibited the accumulation of mitochondrial reactive oxygen species (mtROS) and improved cardiomyocyte damage under oxidative stress. Cardiomyocytes derived from human induced pluripotent embryonic stem cells (iPSC-CMs) and human AC16 cardiomyocytes were chosen for the experiments. Oxidative stress was induced in both cardiomyocyte types using hydrogen peroxide (H2O2), a commonly employed agent. The mtROS accumulation and mitochondrial functional status were assessed by measuring the ROS content, mitochondrial membrane potential, and mitochondrial respiratory chain function. Co-IP experiments were used to analyze whether mtROS promoted protein interactions between TXNIP and NLRP3 and induced NLRP3 inflammasome activation. The results showed that Alda-1 mitigated damage to mitochondrial structure and function under oxidative stress, concurrently reducing the accumulation of mtROS. Co-IP experiments revealed that elevated mtROS levels attenuated the protein interaction between TXNIP and TRX while intensifying the interaction between TXNIP and NLRP3. Consequently, this triggers activation of the NLRP3 inflammasome, leading to cardiomyocyte damage. In contrast, TXNIP knockdown inhibited H2O2-induced myocardial injury and enhanced the therapeutic effects of Alda-1. Collectively, the results show that, in an H2O2 environment, Alda-1 increased the production of ALDH2 activity in cardiomyocytes, hindered the production of mtROS, disrupted the interaction between TXNIP and NLRP3, and alleviated myocardial damage during oxidative stress.
Keywords: Alda‐1; NLRP3; aldehyde dehydrogenase; oxidative stress; thioredoxin‐interacting protein.
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