Ghrelin prevents doxorubicin-induced cardiotoxicity through TNF-alpha/NF-kappaB pathways and mitochondrial protective mechanisms.
We had reported that increased levels of endogenous ghrelin during the progression of doxorubicin-induced cardiomyopathy and heart failure might provide a compensatory self-protective effect. We investigated which pathway(s) produced these protective effects in vitro. Primary cultured cardiomyocytes were induced with doxorubicin in the presence or absence of ghrelin or a tumor necrosis factor-alpha (TNF-alpha) antagonist (etanercept). Ghrelin up-regulated TNF-alpha in a time- and dose-dependent manner. It significantly reduced cell apoptosis and markers of oxidative stress, such as malondialdehyde (MDA) content and lactate dehydrogenase (LDH) activity; it also increased anti-oxidative enzyme activity such as superoxide dismutase (MnSOD) and catalase (CAT), retained mitochondrial membrane potential and energy metabolism compared with doxorubicin alone. Moreover, ghrelin increased mitochondrial anti-apoptosis related gene protein expression such as bcl-2 and MnSOD, reduced cytoplasmic cytochrome C (Cyt C) release and strengthened the activation of NF-kappaB. All these effects were abrogated by etanercept. This suggests ghrelin affects the TNF-alpha/NF-kappaB activation pathways, up-regulating TNF-alpha, to produce anti-oxidative and anti-apoptotic effects that protected cardiomyocytes from doxorubicin-induced cytotoxicity.
Xu
Zhiwei
Z
Department of Pathophysiology, ZhongShan Medical College, Sun Yat-sen University, Guangzhou 510080, China.
Lin
Shiqing
S
Wu
Weikang
W
Tan
Hongmei
H
Wang
Zhi
Z
Cheng
Chao
C
Lu
Lihe
L
Zhang
Xuanhong
X
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D054439:Ghrelin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D054439:Ghrelin; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin