Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells

Eur J Pharmacol. 2014 Dec 15;745:59-68. doi: 10.1016/j.ejphar.2014.09.046. Epub 2014 Oct 14.

Abstract

Endoplasmic reticulum stress (ER stress)-associated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing-3 (NLRP3) signaling is a key event in the endothelial dysfunction. It induces the IL-1β production and thus accounts for inflammation and cell death. Quercetin, luteolin and epigallocatechin gallate (EGCG) are flavonoids with beneficial effects on cardiovascular functions, and we wondered whether these flavonoids protect endothelial functions against ER stress-associated impairments. Palmitate stimulation evoked oxidative stress and then induced TXNIP and NLRP3 inflammasome activation in the endothelial cells. Quercetin, luteolin and EGCG reduced reactive oxygen species production and inhibited TXNIP and NLRP3 inflammasome activation, lead to the downregulation of IL-1β expression. Meanwhile, these agents protected cells from apoptosis by restoration of mitochondrial membrane potential (Δψm) and inhibition of caspase-3 activity. PA stimulation induced inflammation accompanied by the loss of NO production in endothelial cells, but these alterations were reversed by treatment with quercetin, luteolin and EGCG. Co-treatment with AMPK inhibitor compound C diminished the beneficial effects of these flavonoids, suggesting the involvement of AMPK. In conclusion, quercetin, luteolin and EGCG inhibited ER stress-associated TXNIP and NLRP3 inflammasome activation, and thereby protected endothelial cells from inflammatory and apoptotic damage.

Keywords: Endoplasmic reticulum stress; Endothelial cells; Flavonoids; NLRP3; TXNIP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Carrier Proteins / physiology*
  • Catechin / analogs & derivatives*
  • Catechin / pharmacology
  • Cell Line
  • Endoplasmic Reticulum Stress / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Endothelin-1 / genetics
  • Gene Expression / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inflammasomes / drug effects
  • Inflammation / etiology
  • Inflammation / physiopathology
  • Inflammation / prevention & control*
  • Luteolin / pharmacology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Oxidative Stress / drug effects
  • Palmitic Acid / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Quercetin / pharmacology

Substances

  • Carrier Proteins
  • Endothelin-1
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Protein Kinase Inhibitors
  • TXNIP protein, human
  • Palmitic Acid
  • Catechin
  • Quercetin
  • epigallocatechin gallate
  • AMP-Activated Protein Kinases
  • Luteolin