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Published on: August 10, 2018
Walras modulates sex-dependent endoplasmic reticulum stress in cardiomyopathy
Francisco J Martinez-Amaro1, Carlos Garcia-Padilla1,2, Fernando Bonet3,4,5
1Cardiovascular Research Group, Department of Experimental Biology, University of Jaen, Jaen, Spain.
Insights
Long non-coding RNAs (lncRNAs) like Walras are implicated in cardiomyopathies. Walras exacerbates unfolded protein response (UPR) and apoptosis by degrading calumenin, worsening heart disease.
Area of Science:
- Cardiovascular biology
- Molecular genetics
- Cellular stress response
Background:
- Cardiovascular diseases (CVDs) are a leading global cause of death.
- Cardiomyopathies often involve endoplasmic reticulum stress and the unfolded protein response (UPR).
- The role of long non-coding RNAs (lncRNAs) in UPR and cardiomyopathies is an emerging area of research.
Purpose of the Study:
- Investigate the role of specific lncRNAs in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).
- Determine the functional impact of lncRNAs on UPR, apoptosis, and mitochondrial function.
- Elucidate the molecular mechanism by which lncRNAs influence disease progression.
Main Methods:
- Utilized real-time PCR (qPCR), immunochemistry (IMQ), and Western blot (WB).
- Assessed mitochondrial activity using SeaHorse technology and performed mass spectrometry (MS).
- Conducted cell viability assays and analyzed protein-protein interactions.
Main Results:
- Discovered sex-dependent regulation of lncRNAs (Walar, Walaa, Wallrd, Walrad, Walras) in murine DCM and HCM models.
- Demonstrated that Walras overexpression activates UPR, increases apoptosis, and impairs mitochondrial function.
- Identified that Walras interacts with calumenin (CALU), promoting its proteasomal degradation, and its human homologue APO02340.1 has a similar function.
Conclusions:
- Walras and its human homologue APO02340.1 modulate UPR-associated apoptosis via CALU protein regulation.
- These lncRNAs act as detrimental factors in cardiomyopathies by affecting CALU protein turnover.
- Targeting these lncRNAs could offer new therapeutic strategies for heart conditions.
Introduction:
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.
Methods:
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.
Results:
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.
Discussion:
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.
