Silibinin attenuates cardiac hypertrophy and fibrosis through blocking EGFR-dependent signaling.
Cardiac hypertrophy is a major determinant of heart failure. The epidermal growth factor receptor (EGFR) plays an important role in cardiac hypertrophy. Since silibinin suppresses EGFR in vitro and in vivo, we hypothesized that silibinin would attenuate cardiac hypertrophy through disrupting EGFR signaling. In this study, we examined this hypothesis using neonatal cardiac myocytes and fibroblasts induced by angiotensin II (Ang II) and animal model by aortic banding (AB) mice. Our data revealed that silibinin obviously blocked cardiac hypertrophic responses induced by pressure overload. Meanwhile, silibinin markedly reduced the increased generation of EGFR. Moreover, these beneficial effects were associated with attenuation of the EGFR-dependent ERK1/2, PI3K/Akt signaling cascade. We further demonstrated silibinin decreased inflammation and fibrosis by blocking the activation of NF-kappaB and TGF-beta1/Smad signaling pathways in vitro and in vivo. Our results indicate that silibinin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through blocking EGFR activity and EGFR-dependent different intracellular signaling pathways.
Ai
Wen
W
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Zhang
Yan
Y
Tang
Qi-Zhu
QZ
Yan
Ling
L
Bian
Zhou-Yan
ZY
Liu
Chen
C
Huang
He
H
Bai
Xue
X
Yin
Lu
L
Li
Hongliang
H
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
D012838:Silymarin; D000804:Angiotensin II; D000077385:Silybin; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3