Protocatechualdehyde protects oxygen-glucose deprivation/reoxygenation-induced myocardial injury via inhibiting PERK/ATF6α/IRE1α pathway

Eur J Pharmacol. 2021 Jan 15:891:173723. doi: 10.1016/j.ejphar.2020.173723. Epub 2020 Nov 5.

Abstract

Endoplasmic reticulum (ER) stress has been considered as a promising strategy in developing novel therapeutic agents for cardiovascular diseases through inhibiting cardiomyocyte apoptosis. Protocatechualdehyde (PCA) is a natural phenolic compound from medicinal plant Salvia miltiorrhiza with cardiomyocyte protection. However, the potential mechanism of PCA on cardiovascular ischemic injury is largely unexplored. Here, we found that PCA exerted markedly anti-apoptotic effect in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced H9c2 cells (Rat embryonic ventricular H9c2 cardiomyocytes), which was detected by 3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT), lactate dehydrogenase (LDH), Hoechst 33258 and acridine orange/ethidium bromide (AO/EB) assays. PCA also obviously protected cardiomyocytes in myocardial fibrosis model of mice, which was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. Transcriptomics coupled with bioinformatics analysis revealed a complex pharmacological signaling network especially for PCA-mediated ER stress on cardiomyocytes. Further mechanism study suggested that PCA suppressed ER stress via inhibiting protein kinase R-like ER kinase (PERK), inositol-requiring enzyme1α (IRE1α), and transcription factor 6α (ATF6α) signaling pathway through Western blot, DIOC6 and ER-Tracker Red staining, leading to a protective effect against ER stress-mediated cardiomyocyte apoptosis. Taken together, our observations suggest that PCA is a major component from Salvia miltiorrhiza against cardiovascular ischemic injury by suppressing ER stress-associated PERK, IRE1α and ATF6α signaling pathways.

Keywords: Cardiomyocyte apoptosis; Endoplasmic reticulum; Myocardial ischemia; Protocatechualdehyde; Salvia miltiorrhiza; Signaling pathway.

MeSH terms

  • Activating Transcription Factor 6 / genetics
  • Activating Transcription Factor 6 / metabolism*
  • Animals
  • Apoptosis / drug effects*
  • Benzaldehydes / pharmacology*
  • Catechols / pharmacology*
  • Cell Hypoxia
  • Cell Line
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Fibrosis
  • Glucose / deficiency
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Transcriptome
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*

Substances

  • Activating Transcription Factor 6
  • Atf6 protein, rat
  • Benzaldehydes
  • Catechols
  • Ern1 protein, rat
  • Multienzyme Complexes
  • protocatechualdehyde
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases
  • Glucose