title: Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathway.
abstract: 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.
authors.affiliation: Department of Pharmacology, The University of Tokushima School of Medicine, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. yoshizu@basic.med.tokushima-u.ac.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Yuki
authors.initials: Y
authors.lastname: Suzaki
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kirima
authors.forename: Moe
authors.initials: M
authors.lastname: Kyaw
authors.forename: Jae-Hak
authors.initials: JH
authors.lastname: Moon
authors.forename: Junji
authors.initials: J
authors.lastname: Terao
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation; D005609:Free Radicals / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007930:Leucine / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008956:Models, Chemical; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology; D011485:Protein Binding; D011794:Quercetin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D005609:Free Radicals; D020719:Glucuronides; D018808:Transcription Factor AP-1; C443401:quercetin 3-O-glucuronide; D000804:Angiotensin II; D011794:Quercetin; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007930:Leucine