Isorhapontigenin, a new resveratrol analog, attenuates cardiac hypertrophy via blocking signaling transduction pathways.
Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. The hypertrophic process is mediated, in part, by oxidative stress-mediated signaling pathways. We hypothesized that isorhapontigenin (ISO), a new resveratrol analog, inhibits cardiac hypertrophy by blocking oxidative stress and oxidative stress-mediated signaling pathways. We treated cardiomyocytes with angiotensin II (Ang II) with or without ISO and found that ISO inhibited Ang II-induced cardiac hypertrophy. These effects were associated with a decrease in the levels of reactive oxygen species and H2O2 and the content of intracellular malonaldehyde and an increase in the activities of superoxide dismutase and glutathione peroxidase. Ang II induced the phosphorylation of PKC, Erk1/2, JNK, and p38 in cardiomyocytes and such phosphorylation was inhibited by ISO. ISO also blocked the PKC-dependent PI3K-Akt-GSK3beta/p70S6K pathway. These effects lead to direct or indirect inhibition of NF-kappaB and AP-1 activation. Our results revealed that pretreatment with ISO significantly inhibited Ang II-mediated NF-kappaB through affecting the degradation and phosphorylation of IkappaBalpha and the activity of IKKbeta and AP-1 activation by influencing the expression of c-Fos and c-Jun proteins. In addition, we also established the molecular link between activation of PKC and MAPKs and activation of NF-kappaB and AP-1 in cardiomyocytes. We also found that ISO treatment significantly attenuated heart weight/body weight ratio by approximately 25%, decreased posterior wall thickness and left ventricle diastolic and systolic diameters, and increased 10% fractional shortening in an aortic-banded rat model. Furthermore, treatment with ISO significantly decreased cardiac myocyte size and systolic blood pressure. These findings suggest that ISO prevents the development of cardiac hypertrophy through an antioxidant mechanism involving inhibition of different intracellular signaling transduction pathways.
Li
Hong-Liang
HL
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Beijing 100005, Peoples' Republic of China.
Wang
Ai-Bing
AB
Huang
Yue
Y
Liu
De-Pei
DP
Wei
Chiming
C
Williams
G Metville
GM
Zhang
Chan-Na
CN
Liu
Guang
G
Liu
Yu-Qing
YQ
Hao
De-Long
DL
Hui
Rui-Tai
RT
Lin
Mao
M
Liang
Chih-Chuan
CC
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure; D015153:Blotting, Western; D006332:Cardiomegaly / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004789:Enzyme Activation; D005609:Free Radicals; D005979:Glutathione Peroxidase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000196:embryology; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000737:chemistry; D015227:Lipid Peroxidation; D008315:Malondialdehyde / Q000737:chemistry; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008956:Models, Chemical; D032383:Myocytes, Cardiac / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D005609:Free Radicals; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D013267:Stilbenes; D018808:Transcription Factor AP-1; C432307:isorhapontigenin; D000804:Angiotensin II; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007930:Leucine; D000077185:Resveratrol