Sonic hedgehog signaling facilitates pyroptosis in mouse heart following ischemia/reperfusion via enhancing the formation of CARD10-BCL10-MALT1 complex.

in European journal of pharmacology by Ming-Rui Li, Li-Qun Lu, Yi-Yue Zhang, Bi-Feng Yao, Can Tang, Shu-Yan Dai, Xiu-Ju Luo, Jun Peng

TLDR

  • This study investigates how a protein called sonic hedgehog (SHH) can cause damage to the heart during a condition called ischemia/reperfusion (I/R). The study finds that SHH can trigger a process called pyroptosis, which can cause inflammation and damage to the heart. The study also identifies a group of proteins called the CBM complex that can help regulate pyroptosis. The study suggests that inhibiting SHH signaling could be a potential treatment for I/R-induced myocardial injury.

Abstract

Pyroptosis has been found to contribute to myocardial I/R injury, but the exact mechanisms that initiate myocardial pyroptosis are not fully elucidated. Sonic hedgehog (SHH) signaling is activated in heart suffered ischemia/reperfusion (I/R), and intervention of SHH signaling has been demonstrated to protect heart from I/R injury. Caspase recruitment domain-containing protein 10 (CARD10)-B cell lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex could transduce signals from the membrane and induce inflammatory pathways in non-hematopoietic cells, which could be a downstream effector of SHH signaling pathway. This study aims to explore the role of SHH signaling in I/R-induced myocardial pyroptosis and its relationship with the CBM complex. C57BL/6J mice were subjected to 45 min-ischemia followed by 24 h-reperfusion to establish a myocardial I/R model, and H9c2 cells underwent hypoxia/reoxygenation (H/R) to mimic myocardial I/R model in vitro. Firstly, SHH signaling was significantly activated in heart suffered I/R in an autocrine- or paracrine-dependent manner via its receptor PTCH1, and inhibition of SHH signaling decreased myocardial injury via reducing caspase-11-dependent pyroptosis, concomitant with attenuating CBM complex formation. Secondly, suppression of SHH signaling decreased protein kinase C α (PKCα) level, but inhibition of PKCα attenuated CBM complex formation without impacting the protein levels of SHH and PTCH1. Finally, disruption of the CBM complex prevented MALT1 from recruiting of TRAF6, which was believed to trigger the caspase-11-dependent pyroptosis. Based on these results, we conclude that inhibition of SHH signaling suppresses pyroptosis via attenuating PKCα-mediated CARD10-BCL10-MALT1 complex formation in mouse heart suffered I/R.

Overview

  • The study investigates the role of sonic hedgehog (SHH) signaling in ischemia/reperfusion (I/R)-induced myocardial pyroptosis and its relationship with the CBM complex. The study uses C57BL/6J mice subjected to 45 min-ischemia followed by 24 h-reperfusion to establish a myocardial I/R model, and H9c2 cells underwent hypoxia/reoxygenation (H/R) to mimic myocardial I/R model in vitro. The study aims to explore the mechanisms underlying SHH signaling in I/R-induced myocardial pyroptosis and its relationship with the CBM complex.

Comparative Analysis & Findings

  • SHH signaling was significantly activated in heart suffered I/R in an autocrine- or paracrine-dependent manner via its receptor PTCH1, and inhibition of SHH signaling decreased myocardial injury via reducing caspase-11-dependent pyroptosis, concomitant with attenuating CBM complex formation. Suppression of SHH signaling decreased protein kinase C α (PKCα) level, but inhibition of PKCα attenuated CBM complex formation without impacting the protein levels of SHH and PTCH1. Disruption of the CBM complex prevented MALT1 from recruiting of TRAF6, which was believed to trigger the caspase-11-dependent pyroptosis. Based on these results, we conclude that inhibition of SHH signaling suppresses pyroptosis via attenuating PKCα-mediated CARD10-BCL10-MALT1 complex formation in mouse heart suffered I/R.

Implications and Future Directions

  • The study's findings suggest that SHH signaling plays a crucial role in I/R-induced myocardial pyroptosis and its relationship with the CBM complex. The study highlights the importance of SHH signaling in regulating myocardial injury and pyroptosis, and provides insights into the mechanisms underlying these processes. The study also identifies potential therapeutic targets for the treatment of I/R-induced myocardial injury. Future research could further explore the role of SHH signaling in myocardial injury and pyroptosis, and investigate the potential of SHH signaling inhibitors as therapeutic agents for I/R-induced myocardial injury.
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