title: The antioxidant compound tert-butylhydroquinone activates Akt in myocardium, suppresses apoptosis and ameliorates pressure overload-induced cardiac dysfunction.
abstract: Tert-butylhydroquinone (TBHQ) is an antioxidant compound which shows multiple cytoprotective actions. We evaluated the effects of TBHQ on pathological cardiac remodeling and dysfunction induced by chronic overload. Pressure overload was created by transverse aortic constriction (TAC) in male C57BL/6 mice. TBHQ was incorporated in the diet and administered for 4 weeks. TBHQ treatment prevented left ventricular dilatation and cardiac dysfunction induced by TAC, and decreased the prevalence of myocardial apoptosis. The beneficial effects of TBHQ were associated with an increase in Akt activation, but not related to activations of Nrf2 or AMP-activated protein kinase. TBHQ-induced Akt activation was accompanied by increased phosphorylation of Bad, glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin (mTOR). Mechanistically, we showed that in cultured H9c2 cells and primary cardiac myocytes, TBHQ stimulated Akt phosphorylation and suppressed oxidant-induced apoptosis; this effect was abolished by wortmannin or an Akt inhibitor. Blockade of the Akt pathway in vivo accelerated cardiac dysfunction, and abrogated the protective effects of TBHQ. TBHQ also reduced the reactive aldehyde production and protein carbonylation in stressed myocardium. We suggest that TBHQ treatment may represent a novel strategy for timely activation of the cytoprotective Akt pathway in stressed myocardium.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang Liu
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Bi
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital.
authors.forename: Shuangxi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wu
authors.affiliation: 1] Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital [2] Department of Pathophysiology, School of Medicine, Shandong University, Jinan, Shandong Province, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D062186:Arterial Pressure / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006331:Heart Diseases / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D006873:Hydroquinones / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000975:Antioxidants; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C018855:2-tert-butylhydroquinone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D000077191:Wortmannin