P2X4 receptor limits adverse cardiac remodeling following ischemia–reperfusion through regulation of autophagy in cardiac fibroblasts
Cell Communication and Signaling. 2026-07-10; :
DOI: 10.1186/s12964-026-03050-4
Vinhais da Silva AV(1)(2), Strella J(1)(3), Chesseron S(1), Aupart A(1)(3),
Heraud-Meley A(1), Miquelestorena-Standley E(1)(4), Ohresser M(1), Congiu L(5),
Boué-Grabot E(5), Bourguignon T(1)(3), Roger S(1), Chadet S(1), Ivanes F(6)(7).
Author information:
(1)Université de Tours, Inserm UMR1327 ISCHEMIA Membrane Signalling and
Inflammation in Reperfusion Injuries, Tours, 37032, France.
(2)Service de Cardiologie, CHU de Tours, Tours, 37044, France.
(3)Service de Chirurgie Cardiaque, CHU de Tours, Tours, 37044, France.
(4)Service d’Anatomie et Cytologie Pathologiques, CHU de Tours, Tours, 37044,
France.
(5)Université de Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, 33000, France.
(6)Université de Tours, Inserm UMR1327 ISCHEMIA Membrane Signalling and
Inflammation in Reperfusion Injuries, Tours, 37032, France.
.
(7)Service de Cardiologie, CHU de Tours, Tours, 37044, France.
.
BACKGROUND: Pathological ventricular remodeling is an adverse tissue response
following acute myocardial infarction (AMI), characterized by an exaggerated
fibrosis leading to tissue disorganization and chronic heart failure. Cardiac
fibroblasts have a prominent role in the healing process, but also in the
fibrosis development, through their differentiation into myofibroblasts, which
produce the extracellular matrix, in response to ischemia-reperfusion. Recently,
the ATP-gated P2X4 ionotropic receptor has been identified as a key regulator of
macro-autophagy, activated under metabolic challenges.
METHODS: In this study, we investigated the participation of the P2X4 receptor
in the metabolic response of cardiac fibroblasts to ischemia-reperfusion and the
myofibroblast switch. To this end, we submitted a primary culture of cardiac
fibroblasts to an ischemia-reperfusion simulation and assessed autophagic flux,
fibrotic differentiation markers and the correlation to P2X4 expression and
activity. Then, using pharmacological inhibition and siRNA-mediated knockdown
receptor under-expression, we investigated its role in the response of cardiac
fibroblasts to this metabolic challenge. Finally, we validated our findings in
an in vivo murine model of coronary ligation in wild-type and P2rx4-/- mice.
RESULTS: Our results reveal that human cardiac fibroblasts subjected to
simulated ischemia present an increased autophagic activity associated with a
concomitant overexpression of P2X4 and its activity at the plasma membrane of
cells. Pharmacological antagonism of P2X4, or its silencing, impaired autophagy,
as evidenced by the accumulation of autophagy markers, and induced the
expression of fibrotic markers. In an in vivo model of AMI through transient
coronary ligation, P2rx4-/- mice presented the accumulation of autophagic
markers both in healthy and ischemic zones, an extended tissue inflammation and
fibrosis compared to wild type mice.
CONCLUSIONS: This study suggests, for the first time, that the P2X4 receptor may
contribute to steering cardiac fibroblasts toward a healing-associated profile
under ischemia-reperfusion conditions, possibly by modulating autophagic
activity and limiting extensive pro-fibrotic differentiation.
© 2026. The Author(s).
DOI: 10.1186/s12964-026-03050-4
PMID: 42426875
Conflict of interest statement: Declarations. Competing interests: The authors
declare no competing interests.