title: Quercetin inhibits left ventricular hypertrophy in spontaneously hypertensive rats and inhibits angiotensin II-induced H9C2 cells hypertrophy by enhancing PPAR-γ expression and suppressing AP-1 activity.
abstract: BACKGROUND
  Quercetin is the most abundant flavonoid in fruit and vegetables and is believed to attenuate cardiovascular disease. We hypothesized that quercetin inhibits cardiac hypertrophy by blocking AP-1 (c-fos, c-jun) and activating PPAR-γ signaling pathways.
  
  
  RESULTS
  The aim of this study was to identify the mechanism underlying quercetin-mediated attenuation of cardiac hypertrophy. Quercetin therapy reduced blood pressure and markedly reduced the ratio of left ventricular to body weight (LVW/BW) (P<0.05, vs. spontaneously hypertensive rats (SHRs)). In vitro, quercetin also significantly attenuated Ang II-induced H9C2 cells hypertrophy, as indicated by its concentration dependent inhibitory effects on [³H]leucine incorporation into H9C2 cells (64% reduction) and by the reduced hypertrophic surface area in H9C2 cells compared with the Ang II group (P<0.01, vs. Ang II group). Concurrently, we found that PPAR-γ activity was significantly increased in the quercetin-treated group both in vivo and in vitro when analyzed using immunofluorescent or immunohistochemical assays (P<0.05, vs. SHRs or P<0.01, vs. the Ang II group). Conversely, in vivo, AP-1 (c-fos, s-jun) activation was suppressed in the quercetin-treated group, as was the downstream hypertrophy gene, including mRNA levels of ANP and BNP (P<0.05, vs. SHRs). Additionally, both western blotting and real time-PCR demonstrated that PPAR-γ protein and mRNA were increased in the myocardium and AP-1 protein and mRNA were significantly decreased in the quercetin-treated group (P<0.05, vs. SHRs). Furthermore, western blotting and real time-PCR analyses also showed that transfection with PPAR-γ siRNA significantly increased AP-1 signaling and reversed the effects of quercetin inhibition on mRNA expression levels of genes such as ANP and BNP in hypertrophic H9C2 cells.
  
  
  CONCLUSIONS
  Our data indicate that quercetin may inhibit cardiac hypertrophy by enhancing PPAR-γ expression and by suppressing the AP-1 signaling pathway.
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yan
authors.forename: Ji Dong
authors.initials: JD
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Yi Jing
authors.initials: YJ
authors.lastname: Lv
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Gui Lin
authors.initials: GL
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Qiao
authors.forename: Ming
authors.initials: M
authors.lastname: Ren
authors.forename: Xue Feng
authors.initials: XF
authors.lastname: Guo
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D048429:Cell Size; D003094:Collagen / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control*; D008297:Male; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D047495:PPAR gamma; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D003094:Collagen; D011794:Quercetin
references.citation: J Cardiovasc Pharmacol. 1995 Aug;26(2):295-305
references.pmid: 7475055
references.citation: Nature. 2002 Mar 21;416(6878):273-4
references.pmid: 11907561
references.citation: Hypertension. 2000 Oct;36(4):511-6
references.pmid: 11040228
references.citation: Hypertension. 2002 Jan;39(1):81-6
references.pmid: 11799083
references.citation: J Biol Chem. 1999 Nov 5;274(45):32048-54
references.pmid: 10542237
references.citation: Cardiovasc Res. 2009 Feb 1;81(2):370-80
references.pmid: 18952695
references.citation: Diabetes. 2012 May;61(5):1051-61
references.pmid: 22396207
references.citation: Mol Cell Endocrinol. 2007 Jul 15;273(1-2):59-67
references.pmid: 17587490
references.citation: Circ Res. 2000 Sep 29;87(7):596-602
references.pmid: 11009565
references.citation: Oxid Med Cell Longev. 2012;2012:837104
references.pmid: 22685622
references.citation: Curr Opin Lipidol. 1997 Jun;8(3):159-66
references.pmid: 9211064
references.citation: FEBS Lett. 2001 May 4;496(1):12-8
references.pmid: 11343698
references.citation: J Clin Invest. 1995 Aug;96(2):1093-9
references.pmid: 7635944
references.citation: Exp Mol Med. 2009 Apr 30;41(4):226-35
references.pmid: 19299911
references.citation: Pharmacol Res. 2010 Oct;62(4):328-36
references.pmid: 20542118
references.citation: J Appl Physiol (1985). 2001 Aug;91(2):771-6
references.pmid: 11457793
references.citation: Am J Hypertens. 2000 Jan;13(1 Pt 1):74-82
references.pmid: 10678274
references.citation: Circ Res. 1998 Oct 5;83(7):752-60
references.pmid: 9758646
references.citation: J Vet Med Sci. 2009 Jun;71(6):737-43
references.pmid: 19578281
references.citation: Food Chem Toxicol. 1995 Dec;33(12):1061-80
references.pmid: 8847003
references.citation: Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H530-8
references.pmid: 16920808
references.citation: Exp Cell Res. 2012 Aug 1;318(13):1480-91
references.pmid: 22510436
references.citation: J Biol Chem. 2002 Sep 13;277(37):34176-81
references.pmid: 12107164
references.citation: Circulation. 2002 Mar 12;105(10):1240-6
references.pmid: 11889020
references.citation: Adv Exp Med Biol. 2011;701:283-9
references.pmid: 21445799
references.citation: Pharmacogn Mag. 2010 Apr;6(22):135-41
references.pmid: 20668581
references.citation: Biochem Biophys Res Commun. 2002 May 24;293(5):1458-65
references.pmid: 12054679
references.citation: Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1268-75
references.pmid: 21474824
references.citation: Circulation. 2004 Nov 16;110(20):3221-8
references.pmid: 15533863
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Exp Mol Med. 2005 Jun 30;37(3):169-78
references.pmid: 16000870
references.citation: Biomed Pharmacother. 2002 Oct;56(8):407-10
references.pmid: 12442913
references.citation: Can J Physiol Pharmacol. 2001 Aug;79(8):646-53
references.pmid: 11558673
references.citation: J Cell Mol Med. 2009 Aug;13(8A):1549-64
references.pmid: 19778377
references.citation: Atherosclerosis. 2011 Sep;218(1):44-52
references.pmid: 21601209
references.citation: Br J Pharmacol. 2001 May;133(1):117-24
references.pmid: 11325801
references.citation: Hypertension. 2009 Dec;54(6):1353-9
references.pmid: 19822796