Activated gasdermin E (GSDME) amplifies endoplasmic reticulum stress and inflammation in β-adrenoceptor overactivation-induced cardiac injury

Endoplasmic reticulum (ER) stress can induce inflammation in heart failure (HF) by β-adrenoceptor overactivation. In turn, inflammation can trigger ER stress. Cleaved caspase 3 produced during ER stress could induce apoptosis. Gasdermin E (GSDME), when activated by cleaved caspase 3, could induce pyroptosis. We have investigated the role of GSDME in β-adrenoceptor overactivation-induced cardiac injury.

Isoprenaline (ISO) was used to induce β-adrenoceptor overactivation in mice and cultured myocardial cells. PERK inhibitor GSK2606414, si-Gsdme and Gsdme deficiency mice were used to understand the relationship between ER stress and GSDME-mediated pyroptosis/inflammation under β-adrenoceptor overactivation.

The protein levels of cleaved caspase 3 and GSDME-N were increased in cardiac tissues in mice by isoprenaline, while Gsdme knockout inhibited inflammation and cardiac injury. KEGG enrichment analysis indicated that the role of GSDME was potentially associated with ER stress. In vitro, inhibiting PERK-mediated ER stress reduced cleaved caspase 3 and GSDME-N expression and prevented pyroptosis induced by β-adrenoceptor overactivation. Interestingly, knockdown of Gsdme not only prevented pyroptosis and inhibited inflammation but also down-regulated cleaved caspase 3. Finally, either Gsdme knockdown in vitro or Gsdme deficiency in vivo suppressed PERK-driven ER stress.

GSDME functioned both downstream of cleaved caspase 3 to induce pyroptosis/inflammation and upstream of caspase3 to increase caspasen 3 cleavage by enhancing ER stress, suggesting that GSDME was a key molecule to amplify ER stress and inflammation and might play an essential role in the development of HF. GSDME represents a potential pharmacological target for HF.