Journal article
Uncoupling protein 3 mediates H₂O₂ preconditioning-afforded cardioprotection through the inhibition of MPTP opening
Cardiovascular research, Vol.105(2), pp.192-202
02/01/2015
DOI: 10.1093/cvr/cvu256
PMID: 25514931
Abstract
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.
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.
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.
Details
- Title: Subtitle
- Uncoupling protein 3 mediates H₂O₂ preconditioning-afforded cardioprotection through the inhibition of MPTP opening
- Creators
- Yixiong Chen - Shanghai Institutes for Biological SciencesJinlong Liu - Shanghai Institutes for Biological SciencesYanjun Zheng - Shanghai Institutes for Biological SciencesJinxi Wang - Shanghai Institutes for Biological SciencesZhihua Wang - Shanghai Institutes for Biological SciencesShanshan Gu - Shanghai Institutes for Biological SciencesJiliang Tan - Shanghai Institutes for Biological SciencesQing Jing - Shanghai Institutes for Biological SciencesHuangtian Yang - Shanghai Jiao Tong University
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.105(2), pp.192-202
- DOI
- 10.1093/cvr/cvu256
- PMID
- 25514931
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Language
- English
- Date published
- 02/01/2015
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984446409202771
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