Polycystin-1 mitigates damage and regulates CTGF expression through AKT activation during cardiac ischemia/reperfusion

P. Aránguiz, P. Romero, F. Vásquez, R. Flores-Vergara, D. Aravena, G. Sánchez, M. González, I. Olmedo, Z. Pedrozo

Research output: Contribution to journalArticlepeer-review

Abstract

During ischemia/reperfusion (I/R), cardiomyocytes activate pathways that regulate cell survival and death and release factors that modulate fibroblast-to-myofibroblast differentiation. The mechanisms underlying these effects are not fully understood. Polycystin­1 (PC1) is a mechanosensor crucial for cardiac function. This work aims to assess the role of PC1 in cardiomyocyte survival, its role in profibrotic factor expression in cardiomyocytes, and its paracrine effects on I/R-induced cardiac fibroblast function. In vivo and ex vivo I/R and simulated in vitro I/R (sI/R) were induced in wild-type and PC1-knockout (PC1 KO) mice and PC1-knockdown (siPC1) neonatal rat ventricular myocytes (NRVM), respectively. Neonatal rat cardiac fibroblasts (NRCF) were stimulated with conditioned medium (CM) derived from NRVM or siPC1-NRVM supernatant after reperfusion and fibroblast-to-myofibroblast differentiation evaluated. Infarcts were larger in PC1-KO mice subjected to in vivo and ex vivo I/R, and necrosis rates were higher in siPC1-NRVM than control after sI/R. PC1 activated the pro-survival AKT protein during sI/R and induced PC1-AKT-pathway-dependent CTGF expression. Furthermore, conditioned media from sI/R-NRVM induced PC1-dependent fibroblast-to-myofibroblast differentiation in NRCF. This novel evidence shows that PC1 mitigates cardiac damage during I/R, likely through AKT activation, and regulates CTGF expression in cardiomyocytes via AKT. Moreover, PC1-NRVM regulates fibroblast-to-myofibroblast differentiation during sI/R. PC1, therefore, may emerge as a new key regulator of I/R injury-induced cardiac remodeling.

Original languageEnglish
Article number165986
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1867
Issue number1
DOIs
Publication statusPublished - 1 Jan 2021

Keywords

  • AKT
  • Cardiac fibroblast differentiation
  • Cardiac ischemia/reperfusion
  • CTGF/CCN2
  • Polycystin-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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