Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathway

Biochem Biophys Res Commun. 2002 May 24;293(5):1458-65. doi: 10.1016/S0006-291X(02)00407-2.


We previously reported that quercetin, a bioflavonoid belonging to polyphenols, inhibited Angiotensin II (Ang II)-induced vascular smooth muscle cell (VSMC) hypertrophy through the inhibition of c-Jun N-terminal kinase (JNK) activation. However, we recently found that orally administered quercetin appeared in plasma as glucuronide-conjugated forms in rats and humans. Therefore we examined the effect of chemically synthesized quercetin glucuronide on Ang II-induced mitogen-activated protein (MAP) kinase activation and hypertrophy of cultured rat aortic smooth muscle cells (RASMC). Ang II activated extracellular signal-regulated kinase (ERK)1/2, JNK, and p38 in RASMC. Ang II-induced JNK activation was inhibited by quercetin 3-O-beta-d-glucuronide (Q3GA) whereas ERK1/2 and p38 activations were not affected. Q3GA scavenged 1,1-diphenyl-2-picrylhydrazyl radical measured by a method of electron paramagnetic resonance. Q3GA also inhibited Ang II-induced increases in activator protein-1 (AP-1) DNA binding, a downstream transcription factor of JNK. Finally, Ang II-induced [3H]leucine incorporation into RASMC was abolished by Q3GA. These findings suggest that the preventing effect of Q3GA on Ang II-induced VSMC hypertrophy is attributable in part to its inhibitory effect on JNK and the AP-1 signaling pathway. Q3GA would be an active metabolite of quercetin in plasma and may possess a preventing effect for cardiovascular diseases relevant to VSMC growth.

MeSH terms

  • Angiotensin II / metabolism*
  • Animals
  • Dimerization
  • Dose-Response Relationship, Drug
  • Electron Spin Resonance Spectroscopy
  • Enzyme Activation
  • Free Radicals / metabolism
  • Glucuronides / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Leucine / chemistry
  • Leucine / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Chemical
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / pathology
  • Protein Binding
  • Quercetin / analogs & derivatives
  • Quercetin / metabolism
  • Quercetin / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction*
  • Time Factors
  • Transcription Factor AP-1 / chemistry
  • Transcription Factor AP-1 / metabolism*
  • p38 Mitogen-Activated Protein Kinases


  • Free Radicals
  • Glucuronides
  • Transcription Factor AP-1
  • quercetin 3-O-glucuronide
  • Angiotensin II
  • Quercetin
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Leucine