Fig. 8

Proposed working model. The activation of PERK arm of UPR by PERK phosphorylation results in ER Ca²⁺ leak and increase in cytosolic Ca²⁺, most likely due to the activation of calcineurin and Ryanodine Receptors (RyR) from p-PERK. Concomitantly, STIM1 expression is downregulated into the ER membrane of LMNA R321X-cardiomyocytes, thus decreasing the Capacitive Ca²⁺ Entry in these cells, contributing the impairment in handling Ca²⁺(STIM-ORAI). The increase in cytosolic Ca²⁺ together with calcineurin activation induce NFAT translocation from cytosol to nuclei of these cardiomyocytes, most likely contributing to activation of pro-apoptotic pathways. In addition, PERK phosphorylation activates a downstream pathway: eiF2α phosphorylation (p-eiF2α) and ATF4 expression. ATF4 alleviates ER stress. If ER stress is persistent, ATF4 induces the expression of the pro-apoptotic factor CHOP and increases the apoptosis rate in LMNA R321X-cardiomyocytes, as shown by the caspase depended PARP-cleavage in these cardiomyocytes (PARP-CL). The activation of the CHOP-dependent pro-apoptotic pathway is also paralleled by the inhibition of the pro-survival pathway of AKT (p-AKT). Salubrinal and guanabenz act inhibiting eiF2α de-phosphorylation, sustaining ATF4 expression in the direction of ER stress alleviation. Empagliflozin, instead, acts directly inhibiting PERK activation. All drugs shutting down the PERK pathway of the UPR recover ER Ca²⁺ leaks, STIM1 downregulation, cytosolic Ca²⁺ overload and the downstream pro-apoptotic responses. The cartoon has been created with BioRender.com