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.

Nrf2 Activation Provides Atheroprotection in Diabetic Mice Through Concerted Upregulation of Antioxidant, Anti-inflammatory, and Autophagy Mechanisms

“…Associated with Nrf2 induction in diabetic mouse aorta, tBHQ treatment reduced the area, extension, lipid content and inflammatory milieu of atherosclerotic plaques, independently of changes in blood glycemia and lipids. Our results are in agreement with the previously reported effect of tBHQ in ischemic stroke ( Shih et al, 2005 ) and cardiac dysfunction ( Zhang et al, 2015 ) and support the use of Nrf2 activators as potential therapy for diabetic complications ( Xue et al, 2008 ; Jiang et al, 2010 ; Tan and de Haan, 2014 ; Tan et al, 2014 ).…”

“…Neuroprotective actions have been also reported in experimental models of traumatic brain injury ( Saykally et al, 2012 ; Chandran et al, 2017 ), Alzheimer’s disease ( Akhter et al, 2011 ), and neonatal hypoxic-ischemic brain damage ( Zhang et al, 2018 ). Moreover, tBHQ ameliorates overload-induced cardiac dysfunction by suppressing apoptosis and promoting autophagy ( Lin et al, 2014 ; Zhang et al, 2015 ), and also improves angiogenesis and heart function in a model of myocardial infarction ( Zhou et al, 2017 ). tBHQ results from butylated hydroxyanlisole biotransformation, and readily auto-oxidizes to an electrophilic metabolite, tert-butylbenzoquinone (tBQ).…”

Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection

“…We conclude that other mechanisms besides Nrf2 and IL-17D could regulate certain innate immune cell infiltration after tBHQ injection. Other studies have found that tBHQ can also activate Akt 26 and its downstream target endothelial nitric oxide synthase (eNOS) 27 . It is possible that tBHQ acts through one of these or another yet unknown pathway in our system.…”

Tert-butylhydroquinone attenuates the ethanol-induced apoptosis of and activates the Nrf2 antioxidant defense pathway in H9c2 cardiomyocytes

“…Independently of Nrf2 activation, other protective mechanisms of tBHQ are also involved in the induction of autophagy ( 44 , 45 ). In addition, a recent study demonstrated that tBHQ activated Akt rather than Nrf2 to suppress apoptosis ( 46 ). In our study, pre-treatment with tBHQ significantly restored the level of Nrf2 protein ( Fig.…”