PM2.5 induces cardiac malformations via PI3K/akt2/mTORC1 signaling pathway in zebrafish larvae

Growing evidence indicates that maternal fine particulate matter (PM2.5) exposure is linked with congenital heart diseases in the offspring. To explore the underlying molecular mechanisms, we tested the effects of a number of pharmaceutical inhibitors, and found that suppressing the PI3K/akt signaling pathway had a protective effect against cardiac defects in zebrafish larvae exposed to extractable organic matter (EOM) from PM2.5. Using genetic knockdown and a specific akt2 pharmacological inhibitor, CCT128930, we demonstrated that akt2 activation is essential to EOM-induced heart malformations. Next, we found that the EOM-induced akt2 overactivation enhances intracellular reactive oxygen species (ROS)/mitochondrial ROS production, decreases mitochondrial membrane potential levels, and elicits intrinsic apoptosis in the heart of zebrafish embryos. In addition, EOM-induced akt2 activation decreased active β-catenin levels and inhibited the expression of Wnt target genes axin2 and nkx2.5. We further demonstrated that mTORC1 phosphorylation mediates the adverse effects of akt2 on intrinsic apoptosis and canonical Wnt signaling in the heart of zebrafish larvae exposed to EOM. Moreover, EOM-induced akt2 activation is mediated via aryl hydrocarbon receptor (AHR)/ROS-induced PTEN inhibition. In conclusion, our results indicate that PM2.5 activates PI3K/akt2/mTORC1 signaling via AHR/ROS-induced PTEN suppression, which leads to mitochondrial-mediated intrinsic apoptosis and Wnt signaling suppression, resulting in cardiac defects in zebrafish larvae.

 

Comments:

Wow, it seems like your research delves into the intricate molecular mechanisms behind the association between maternal exposure to fine particulate matter (PM2.5) and congenital heart diseases in offspring. The findings about the involvement of the PI3K/akt signaling pathway and its impact on cardiac defects in zebrafish larvae exposed to PM2.5 are quite fascinating.

The cascade of events you've outlined, from the activation of akt2 leading to increased reactive oxygen species (ROS) production and mitochondrial dysfunction to the inhibition of Wnt signaling and induction of intrinsic apoptosis, presents a comprehensive understanding of how PM2.5 exposure might induce cardiac malformations.

The involvement of mTORC1 phosphorylation in mediating the adverse effects of akt2 on intrinsic apoptosis and Wnt signaling, along with the revelation about the role of aryl hydrocarbon receptor (AHR)/ROS-induced PTEN inhibition in activating the PI3K/akt2/mTORC1 pathway, provides a comprehensive picture of the molecular pathway involved.

Understanding these mechanisms could potentially lead to the development of targeted interventions or preventive strategies to mitigate the adverse effects of PM2.5 exposure during pregnancy on fetal heart development.

Related Products

Cat.No.	Product Name	Information
S2635	CCT128930	CCT128930 is a potent, ATP-competitive and selective inhibitor of Akt2 with IC50 of 6 nM in a cell-free assay, 28-fold greater selectivity for Akt2 than the closely related PKA kinase. CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition. High dose of CCT128930 triggers cell apoptosis in HepG2 cells.

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Autophagy Apoptosis related Akt