Walras modulates sex-dependent endoplasmic reticulum stress in cardiomyopathy

Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year. Most heart cardiomyopathies result in an increased need for protein production that translates into an increased endoplasmic reticulum stress and therefore in the activation of the unfolded protein response pathway (UPR). The sustained activation of this pathway produces cell death and worsens the course of the disease. The role of lncRNAs in UPR signalling and their impact in several cardiomyopathies is beginning to be addressed.

To conduct our study we have performed real time PCR (qPCR), immunochemistry (IMQ), SeaHorse mithocondrial activity, Western blot (WB), Mass spectrometry (MS) and cell viability analysis.

Our results demonstrate a sex-dependent regulation of Walar, Walaa, Wallrd, Walrad and Walras lncRNAs in different dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) murine experimental models. Functional assays demonstrated that Walras overexpression leads to unfolded protein response (UPR) pathway activation and increased apoptosis, and additionally it also impairs mitochondrial function. Mechanistically, Walras physically interacts with calumenin (CALU), repressing its protein levels by promoting proteosomal degradation. Finally, we proved that APO02340.1, a Walras human homologue exerts a similar role.

Our data demonstrate that Walras and APO02340.1 modulate UPR associated apoptosis by regulating CALU protein turnover and thus acting as deletereous factors in several cardiomyophaties.