Yixiong Chen1, Jinlong Liu1, Yanjun Zheng1, Jinxi Wang1, Zhihua Wang1, Shanshan Gu1, Jiliang Tan1, Qing Jing1, Huangtian Yang2. 1. Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), 320 Yue Yang Road, Biological Research Building A, Shanghai 200031, China. 2. Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), 320 Yue Yang Road, Biological Research Building A, Shanghai 200031, China htyang@sibs.ac.cn.
Abstract
AIMS: Uncoupling protein 3 (UCP3), located in the mitochondrial inner membrane, is cardioprotective, but its mechanisms of preserving mitochondrial function during ischaemia/reperfusion (I/R) are not fully understood. This study investigated whether UCP3 mediates/mimics the cardioprotection of H₂O₂ preconditioning (H₂O₂PC) against I/R injury and the downstream pathway that mediates H₂O₂PC- and UCP3-afforded cardioprotection. METHODS AND RESULTS: H₂O₂PC at 20 µM for 5 min significantly improved post-ischaemic functional recovery and reduced lactate dehydrogenase (LDH) release and infarct size with concurrently up-regulated UCP3 expressions in perfused rat hearts subjected to global no-flow I/R. These protections were blocked by UCP3 knockdown with short hairpin RNA but mimicked by UCP3 overexpression. Consistently, H₂O₂PC-attenuated I/R-induced cytosolic and mitochondrial Ca(2+) overload, Ca(2+) transient suppression, mitochondrial reactive oxygen species burst, and loss of mitochondrial inner membrane potential were reversed by UCP3 knockdown but mimicked by UCP3 overexpression. Moreover, co-immunoprecipitation assay revealed an interaction of UCP3 with the mitochondrial permeability transition pore (mPTP) component, adenine nucleotide translocator (ANT), while the cardioprotection induced by H₂O₂PC- and UCP3 overexpression in mitochondria, cardiac function, and cell survival was abolished by atractyloside, a mPTP opener binding to ANT, and partially inhibited by a PI3K/Akt inhibitor wortmannin. Furthermore, H₂O₂PC up-regulated the phosphorylation of Akt, and glycogen synthase kinase 3β was blocked by UCP3 knockdown but mimicked by UCP3 overexpression. CONCLUSION: UCP3 mediates the cardioprotection of H₂O₂PC against I/R injury by preserving the mitochondrial function through inhibiting mPTP opening via the interaction with ANT and the PI3K/Akt pathway. Our findings reveal novel mechanisms of UCP3 in the cardioprotection. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Uncoupling protein 3 (UCP3), located in the mitochondrial inner membrane, is cardioprotective, but its mechanisms of preserving mitochondrial function during ischaemia/reperfusion (I/R) are not fully understood. This study investigated whether UCP3 mediates/mimics the cardioprotection of H₂O₂ preconditioning (H₂O₂PC) against I/R injury and the downstream pathway that mediates H₂O₂PC- and UCP3-afforded cardioprotection. METHODS AND RESULTS: H₂O₂PC at 20 µM for 5 min significantly improved post-ischaemic functional recovery and reduced lactate dehydrogenase (LDH) release and infarct size with concurrently up-regulated UCP3 expressions in perfused rat hearts subjected to global no-flow I/R. These protections were blocked by UCP3 knockdown with short hairpin RNA but mimicked by UCP3 overexpression. Consistently, H₂O₂PC-attenuated I/R-induced cytosolic and mitochondrial Ca(2+) overload, Ca(2+) transient suppression, mitochondrial reactive oxygen species burst, and loss of mitochondrial inner membrane potential were reversed by UCP3 knockdown but mimicked by UCP3 overexpression. Moreover, co-immunoprecipitation assay revealed an interaction of UCP3 with the mitochondrial permeability transition pore (mPTP) component, adenine nucleotide translocator (ANT), while the cardioprotection induced by H₂O₂PC- and UCP3 overexpression in mitochondria, cardiac function, and cell survival was abolished by atractyloside, a mPTP opener binding to ANT, and partially inhibited by a PI3K/Akt inhibitor wortmannin. Furthermore, H₂O₂PC up-regulated the phosphorylation of Akt, and glycogen synthase kinase 3β was blocked by UCP3 knockdown but mimicked by UCP3 overexpression. CONCLUSION:UCP3 mediates the cardioprotection of H₂O₂PC against I/R injury by preserving the mitochondrial function through inhibiting mPTP opening via the interaction with ANT and the PI3K/Akt pathway. Our findings reveal novel mechanisms of UCP3 in the cardioprotection. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Jimmy Zhang; Sergiy M Nadtochiy; William R Urciuoli; Paul S Brookes Journal: Am J Physiol Heart Circ Physiol Date: 2015-10-30 Impact factor: 4.733
Authors: Lukas J Motloch; Tina Gebing; Sara Reda; Astrid Schwaiger; Martin Wolny; Uta C Hoppe Journal: J Membr Biol Date: 2016-07-01 Impact factor: 1.843