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Pathological remodelling of the left ventricle and emerging roles for the P2X4 receptor: A molecular switch for cellular stress.
- Source :
- Archives of Cardiovascular Diseases; 2024 Supplement, Vol. 117, pS182-S182, 1p
- Publication Year :
- 2024
-
Abstract
- Pathological left ventricular remodeling is a complex process involving the architectural disorganisation of cardiac tissue following a myocardial infarction. This is characterised by the exaggerated development of fibrotic scar tissue that can lead to heart failure. In an attempt to understand this, we hypothesised that an altered response of cardiac fibroblasts, subjected to cellular stress-induced by coronary occlusion, could be involved in this pathological remodelling. Their response is orchestrated by molecular switches that enable them to detect their environment, survive during cellular stress and regulates their response. Among these molecular switches, P2X4 appears to play a pivotal role due to its sensitivity to extracellular ATP, a molecule released during cellular stress that modulates the tissue response to the environment. Interestingly, P2X4, which can also be found at the membrane of lysosomes, is involved in regulating autophagy, a critical pathway for cell survival in the event of nutrient and oxygen deprivation. Elucidate P2X4 role in governing the behavior of cardiac fibroblasts during oxygen and nutrient deprivation, and its potential contribution to cardiac remodeling. Characterizing the response of a primary culture of cardiac fibroblasts to oxygen and nutrient deprivation stress: assessing fibrosis and autophagy markers together with P2X4 expression by Western Blot The impact of P2X4 is further elucidated using siRNA methodology and in vivo experiments involving coronary ligation in P2X4 KO mice. Our results suggest that fibroblasts subjected to nutrient and oxygen deprivation differentiate towards a myofibroblastic profile, the initiator of fibrosis. At the same time, autophagy markers decrease, indicating an increased autophagic flux. This autophagic flux is accompanied by protein overexpression of P2X4 in these cells. When cells loose P2X4 expression, whose subjected to stress overexpress fibrotic markers compared with siCTL. Together autophagy markers increased, suggesting a disruption of autophagic flow. Using a coronary ligation model, we can see that the at-risk areas of the ligated hearts of KO P2X4 mice show an accumulation of fibrosis markers as well as those studied for autophagy. Our work reveals P2X4 role in orienting cardiac fibroblasts towards a healing profile when subjected to stress-induced deprivation. Its role is potentially explained by the modulation of autophagic flux, disturbing the balance in the elimination of pro-fibrotic factors. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 18752136
- Volume :
- 117
- Database :
- Supplemental Index
- Journal :
- Archives of Cardiovascular Diseases
- Publication Type :
- Academic Journal
- Accession number :
- 178045417
- Full Text :
- https://doi.org/10.1016/j.acvd.2024.05.044