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Ablation of Akt2 prevents paraquat-induced myocardial mitochondrial injury and contractile dysfunction: Role of Nrf2.
Toxicol Lett. 2017 Mar 05; 269:1-14.TL

Abstract

Paraquat is a quaternary nitrogen herbicide triggering oxidative stress, mitochondrial damage and multi-organ injuries including hearts. To date, effective measure to combat paraquat toxicity is still lacking. Recent evidence has revealed a role for Akt in cardiac homeostasis. To this end, this study was designed to examine the role of Akt2 in acute paraquat exposure-induced cardiac contractile and mitochondrial injury using a unique murine model of Akt2 knockout. Cardiac contractile and intracellular Ca2+ properties were evaluated. Mitochondrial integrity, ROS production, lipid peroxidation, ER stress and apoptosis were evaluated using aconitase assay, citrate synthase activity, DHE staining, mitochondrial permeation pore opening, 4-hydroxy-nonenal (4-HNE) and Western blot. Our results revealed compromised echocardiographic, contractile and intracellular Ca2+ handling properties along with overt mitochondrial damage (reduced levels of PGC-1α, aconitase, citrate synthase activity and NAD+) in mice challenged with paraquat (45mg/kg, single injection, i.p.), the effects of which were attenuated by Akt ablation. Paraquat triggered O2- production, lipid peroxidation and apoptosis as evidenced by increased DHE staining, 4-HNE, caspase-3 activity, Bax and reduced Bcl-2 levels in association with unchanged ER stress. The redox signaling molecule nuclear factor erythroid related factor 2 (Nrf2) was upregulated in response to paraquat challenge. Findings from in vitro study revealed that stimulation of Nrf2 using sulforaphane (10μM) negated Akt2 ablation-offered beneficial effect against paraquat whereas inhibition of Nrf2 using luteolin (20μM) mimicked Akt2 ablation-induced beneficial effect against paraquat challenge. Taken together, our data indicate that Akt2 ablation may protect against paraquat toxicity-induced cardiac contractile defect and apoptosis possibly via regulation of Nrf2 activation and mitochondrial homeostasis.

Authors+Show Affiliations

Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA; Department of Anesthesiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.Department of Anesthesiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: jren@uwyo.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28115273

Citation

Wang, Shuyi, et al. "Ablation of Akt2 Prevents Paraquat-induced Myocardial Mitochondrial Injury and Contractile Dysfunction: Role of Nrf2." Toxicology Letters, vol. 269, 2017, pp. 1-14.
Wang S, Zhu X, Xiong L, et al. Ablation of Akt2 prevents paraquat-induced myocardial mitochondrial injury and contractile dysfunction: Role of Nrf2. Toxicol Lett. 2017;269:1-14.
Wang, S., Zhu, X., Xiong, L., & Ren, J. (2017). Ablation of Akt2 prevents paraquat-induced myocardial mitochondrial injury and contractile dysfunction: Role of Nrf2. Toxicology Letters, 269, 1-14. https://doi.org/10.1016/j.toxlet.2017.01.009
Wang S, et al. Ablation of Akt2 Prevents Paraquat-induced Myocardial Mitochondrial Injury and Contractile Dysfunction: Role of Nrf2. Toxicol Lett. 2017 Mar 5;269:1-14. PubMed PMID: 28115273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ablation of Akt2 prevents paraquat-induced myocardial mitochondrial injury and contractile dysfunction: Role of Nrf2. AU - Wang,Shuyi, AU - Zhu,Xiaoling, AU - Xiong,Lize, AU - Ren,Jun, Y1 - 2017/01/20/ PY - 2016/09/12/received PY - 2016/12/30/revised PY - 2017/01/15/accepted PY - 2017/1/25/pubmed PY - 2017/3/23/medline PY - 2017/1/25/entrez KW - Akt2 KW - Cardiac KW - Contraction KW - Mitochondrial homeostasis KW - Nrf2 KW - Paraquat SP - 1 EP - 14 JF - Toxicology letters JO - Toxicol Lett VL - 269 N2 - Paraquat is a quaternary nitrogen herbicide triggering oxidative stress, mitochondrial damage and multi-organ injuries including hearts. To date, effective measure to combat paraquat toxicity is still lacking. Recent evidence has revealed a role for Akt in cardiac homeostasis. To this end, this study was designed to examine the role of Akt2 in acute paraquat exposure-induced cardiac contractile and mitochondrial injury using a unique murine model of Akt2 knockout. Cardiac contractile and intracellular Ca2+ properties were evaluated. Mitochondrial integrity, ROS production, lipid peroxidation, ER stress and apoptosis were evaluated using aconitase assay, citrate synthase activity, DHE staining, mitochondrial permeation pore opening, 4-hydroxy-nonenal (4-HNE) and Western blot. Our results revealed compromised echocardiographic, contractile and intracellular Ca2+ handling properties along with overt mitochondrial damage (reduced levels of PGC-1α, aconitase, citrate synthase activity and NAD+) in mice challenged with paraquat (45mg/kg, single injection, i.p.), the effects of which were attenuated by Akt ablation. Paraquat triggered O2- production, lipid peroxidation and apoptosis as evidenced by increased DHE staining, 4-HNE, caspase-3 activity, Bax and reduced Bcl-2 levels in association with unchanged ER stress. The redox signaling molecule nuclear factor erythroid related factor 2 (Nrf2) was upregulated in response to paraquat challenge. Findings from in vitro study revealed that stimulation of Nrf2 using sulforaphane (10μM) negated Akt2 ablation-offered beneficial effect against paraquat whereas inhibition of Nrf2 using luteolin (20μM) mimicked Akt2 ablation-induced beneficial effect against paraquat challenge. Taken together, our data indicate that Akt2 ablation may protect against paraquat toxicity-induced cardiac contractile defect and apoptosis possibly via regulation of Nrf2 activation and mitochondrial homeostasis. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/28115273/Ablation_of_Akt2_prevents_paraquat_induced_myocardial_mitochondrial_injury_and_contractile_dysfunction:_Role_of_Nrf2_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(17)30009-7 DB - PRIME DP - Unbound Medicine ER -