Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1α signalling
Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1α signalling
复制标题
右美托咪定后治疗通过 HIF-1 α 信号传导抑制细胞凋亡，减轻心脏缺血/再灌注损伤
DOI：
10.1111/jcmm.14795
复制
发表时间：
2019-11-03
影响因子：
5.3
通讯作者：
Ji, Fu-hai
中科院分区：
文献类型：
--
作者：
Peng, Ke;Chen, Wei-rong;Ji, Fu-hai
缺氧诱导因子1 α（HIF-1 α）在心肌缺血/再灌注（I/R）损伤的细胞凋亡过程中起着重要作用。本研究旨在探讨右美托咪定（dexmedetomidine，DEX）后处理是否能通过调节HIF-1 α信号通路在体内外对抗I/R诱导的心肌细胞凋亡。结扎大鼠左前降支30 min，再灌注6 h，造成心肌缺血/再灌注（I/R），缺氧/复氧（H/R）造成心肌细胞缺氧/复氧（H/R）。在再灌注或复氧开始时给予右美托咪定可减轻I/R诱导的心肌损伤或H/R诱导的细胞死亡，减轻线粒体功能障碍，减少凋亡心肌细胞的数量，抑制HIF-1 α的活化，并调节凋亡相关蛋白的表达，包括BCL-2、BAX、BNIP 3、裂解的caspase-3和裂解的PARP。相反，HIF-1 α脯氨酰羟化酶-2抑制剂IOX 2在体内和体外部分阻断DEX介导的心脏保护作用。从机制上讲，DEX在转录后水平下调HIF-1 α的表达，并抑制靶基因BNIP 3的转录激活。DEX后处理可在体内保护心脏I/R损伤，在体外保护H/R损伤。这些作用至少部分是通过靶向HIF-1 α信号传导抑制细胞凋亡介导的。
Hypoxia-inducible factor 1 alpha (HIF-1 alpha) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1 alpha signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1 alpha and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1 alpha prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1 alpha expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1 alpha signalling.