Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells.
Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in various cardiovascular diseases. Ang II-induced cellular events have been implicated, in part, in the activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that daily intake of bioflavonoids belonging to polyphenols reduces the incidence of ischemic heart diseases (known as "French paradox"), the precise mechanisms of efficacy have not been elucidated. Thus, we hypothesized that bioflavonoids may affect Ang II-induced MAP kinase activation in cultured rat aortic smooth muscle cells (RASMC). Our findings showed that Ang II stimulated rapid and significant activation of extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and p38 in RASMC. Ang II-induced JNK activation was inhibited by 3,3',4',5,7-pentahydroxyflavone (quercetin), a major bioflavonoid in foods of plant origin, whereas ERK1/2 and p38 activation by Ang II were not affected by quercetin. Ang II caused a rapid tyrosine phosphorylation of Src homology and collagen (Shc), which was inhibited by quercetin. Quercetin also inhibited Ang II-induced Shc.p85 association and subsequent activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway in RASMC. Furthermore, LY294002, a PI3-K inhibitor and a quercetin derivative, inhibited Ang II-induced JNK activation as well as Akt phosphorylation. Finally, Ang II-induced [(3)H]leucine incorporation was abolished by both quercetin and LY294002. These findings suggest that the preventing effect of quercetin on Ang II-induced VSMC hypertrophy are attributable, in part, to its inhibitory effect on Shc- and PI3-K-dependent JNK activation in VSMC. Thus, inhibition of JNK by quercetin may imply its usefulness for the treatment of cardiovascular diseases relevant to VSMC growth.
Yoshizumi
M
M
Department of Pharmacology, The University of Tokushima School of Medicine, Tokushima, Japan. yoshizu@basic.med.tokushima-u.ac.jp
Tsuchiya
K
K
Kirima
K
K
Kyaw
M
M
Suzaki
Y
Y
Tamaki
T
T
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007930:Leucine / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains
D000804:Angiotensin II; D002867:Chromones; D003094:Collagen; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D007930:Leucine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011794:Quercetin; D014316:Tritium; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C494920:Akt1 protein, rat