CCN1 triggers adaptive autophagy in cardiomyocytes to curb its apoptotic activities

Bor Chyuan Su, Pei Ling Hsu, Fan E. Mo

Research output: Contribution to journalArticlepeer-review

Abstract

Autophagy occurs at basal levels for cellular homeostasis under normal conditions and is increased in response to nutrient starvation or stress to ensure cell survival. However, excessive autophagy can be deleterious to cardiomyocytes. CCN1/Cyr61, a matricellular protein, is expressed in the stressed heart to induce cardiomyopathy. The role of autophagy in CCN1-associated cardiotoxicity was not clear. Here, we found that autophagy was induced in the myocardium of the isoproterenol (ISO; 100 mg/kg/day for 5 days; s.c.) treated mice, where CCN1 expression is colocalized. The knock-in mice carrying an integrin α6β1-binding-defective mutant allele Ccn1-dm were resistant to the ISO-induced cardiac injury and autophagy. Our in vitro studies demonstrated that CCN1 dose- and time-dependently induced GFP-LC3-labeled autophagosome formation in rat cardiomyoblast H9c2 cells. The formation of autolysosomes in response to CCN1 (5 μg/ml; 3 h) treatment was identified by the acridine orange staining. The autophagy induction was confirmed by the elevated protein levels of Beclin 1, Atg5, and LC3-II, and the decrease of p62. Inhibition of autophagy by 3-methyladenine or by silencing Atg5 gene enabled CCN1-induced apoptosis in H9c2 cells, suggesting a protective role of autophagy. CCN1 binds to integrin α6β1 to induce autophagy through reactive oxygen species, and the activation of ERK and JNK. Furthermore, mitophagy was observed after CCN1 treatment for the clearance of depolarized mitochondria. Together, these results demonstrated that autophagy is induced in response to CCN1/α6β1 signaling in cardiomyocytes to alleviate CCN1-associated cardiotoxicity.

Original languageEnglish
Pages (from-to)93-100
Number of pages8
JournalJournal of Cell Communication and Signaling
Volume14
Issue number1
DOIs
Publication statusPublished - Mar 1 2020

Keywords

  • Apoptosis
  • Autophagy
  • CCN1
  • Integrin α6β1
  • Mitophagy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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