Uncoupling protein 3 mediates H2O2 preconditioning-afforded cardioprotection through the inhibition of MPTP opening
Uncoupling protein 3 mediates H2O2 preconditioning-afforded cardioprotection through the inhibition of MPTP opening
复制标题
解偶联蛋白 3 通过抑制 MPTP 开放介导 H2O2 预处理提供的心脏保护作用
DOI：
10.1093/cvr/cvu256
复制
发表时间：
2015-02-01
影响因子：
10.8
通讯作者：
Yang, Huangtian
中科院分区：
文献类型：
--
作者：
Chen, Yixiong;Liu, Jinlong;Yang, Huangtian
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 mu M 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 Ca2+ overload, Ca2+ 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 3 beta 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.
