Effects of dexmedetomidine postconditioning on myocardial ischemia and the role of the PI3K/Akt-dependent signaling pathway in reperfusion injury

被引:76
作者
Cheng, Xiang Yang [1 ,2 ]
Gu, Xiao Yu [2 ,3 ]
Gao, Qin [3 ,4 ]
Zong, Qiao Feng [3 ]
Li, Xiao Hong [2 ]
Zhang, Ye [1 ]
机构
[1] Anhui Med Univ, Affiliated Hosp 2, Dept Anesthesiol, 678 Fu Rong Rd, Hefei 230601, Anhui, Peoples R China
[2] Bengbu Med Coll, Affiliated Hosp 1, Dept Anesthesiol, Bengbu 233004, Anhui, Peoples R China
[3] Bengbu Med Coll, Dept Physiol, Bengbu 233030, Anhui, Peoples R China
[4] Bengbu Med Coll, Anhui Key Lab Tissue Transplantat, Bengbu 233030, Anhui, Peoples R China
关键词
dexmedetomidine; cardioprotection; apoptosis; ischemia/reperfusion; phosphatidylinositol-3 kinase/protein kinase B signaling pathway; BCL-2 FAMILY PROTEINS; ISCHEMIA/REPERFUSION INJURY; AWAKE CRANIOTOMY; DYSFUNCTION; APOPTOSIS; PROTECTS; TARGETS; HEARTS;
D O I
10.3892/mmr.2016.5345
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The present study aimed to determine whether post-ischemic treatment with dexmedetomidine (DEX) protected the heart against acute myocardial ischemia/reperfusion (I/R)-induced injury in rats. The phosphatidylinositol-3 kinase/protein kinase B(PI3K/Akt)-dependent signaling pathway was also investigated. Male Sprague Dawley rats (n=64) were subjected to ligation of the left anterior descending artery (LAD), which produced ischemia for 25 min, followed by reperfusion. Following LAD ligation, rats were treated with DEX (5, 10 and 20 mu g/kg) or underwent post-ischemic conditioning, which included three cycles of ischemic insult. In order to determine the role of the PI3K/Akt signaling pathway, wortmannin (Wort), a PI3K inhibitor, was used to treat a group of rats that had also been treated with DEX (20 mu g/kg). Post-reperfusion, lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzymes (CK-MB), superoxide dismutase (SOD) and malondialdehyde (MDA) serum levels were measured using an ultraviolet spectrophotometer. The protein expression levels of phosphorylated (p)-Akt, Ser9-p-glycogen synthase kinase-3 beta (p-GSK-3 beta) and cleaved caspase-3 were detected in heart tissue by western blotting. The mRNA expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected using reverse transcription-polymerase chain reaction. At the end of the experiment, the hearts were removed and perfused in an isolated perfusion heart apparatus with Evans blue (1%) in order to determine the non-ischemic areas. The risk and infarct areas of the heart were not dyed. As expected, I/R induced myocardial infarction, as determined by the increased serum levels of cTnI, CK-MB and MDA, and the decreased levels of SOD. Post-ischemic treatment with DEX increased the expression levels of p-Akt and p-GSK-3 beta, whereas caspase-3 expression was reduced following DEX treatment compared with in the I/R group. Compared with the I/R group, the ratio of Bcl-2/Bax at the mRNA level was elevated in the DEX and ischemic post-conditioning groups, whereas the expression levels of Bax were decreased. Conversely, the effects of DEX were attenuated by Wort. These results indicated that, similar to post-ischemic conditioning, post-ischemic treatment with DEX protects the heart against I/R via the PI3K/Akt-dependent signaling pathway, possibly by activating GSK-3 beta.
引用
收藏
页码:797 / 803
页数:7
相关论文
共 18 条
[1]   Hydrogen sulfide ameliorates cardiovascular dysfunction induced by cecal ligation and puncture in rats [J].
Abdelrahman, R. S. ;
El-Awady, M. S. ;
Nader, M. A. ;
Ammar, E. M. .
HUMAN & EXPERIMENTAL TOXICOLOGY, 2015, 34 (10) :953-964
[2]   Awake craniotomy with dexmedetomidine in pediatric patients [J].
Ard, J ;
Doyle, W ;
Bekker, A .
JOURNAL OF NEUROSURGICAL ANESTHESIOLOGY, 2003, 15 (03) :263-266
[3]   Regulation of mitochondrial morphological dynamics during apoptosis by Bcl-2 family proteins - A key in Bak? [J].
Brooks, Craig ;
Dong, Zheng .
CELL CYCLE, 2007, 6 (24) :3043-3047
[4]   Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review) [J].
Cai, Ye ;
Xu, Hui ;
Yan, Jia ;
Zhang, Lei ;
Lu, Yi .
MOLECULAR MEDICINE REPORTS, 2014, 9 (05) :1542-1550
[5]   Early identification of permanent myocardial damage after coronary surgery is aided by repeated measurements of CK-MB [J].
Dahlin, LG ;
Kågedal, B ;
Nylander, E ;
Olin, C ;
Rutberg, H ;
Svedjeholm, R .
SCANDINAVIAN CARDIOVASCULAR JOURNAL, 2002, 36 (01) :35-40
[6]   Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK/GSK-3β pathway independent of PI3K/Akt [J].
He, Shu-Fang ;
Jin, Shi-Yun ;
Wu, Hao ;
Wang, Bin ;
Wu, Yun-Xiang ;
Zhang, Shu-Jie ;
Irwin, Michael G. ;
Wong, Tak-Ming ;
Zhang, Ye .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2015, 288 (03) :349-358
[7]   Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart [J].
Ibacache, Mauricio ;
Sanchez, Gina ;
Pedrozo, Zully ;
Galvez, Felipe ;
Humeres, Claudio ;
Echevarria, Ghislaine ;
Duaso, Juan ;
Hassi, Mario ;
Garcia, Lorena ;
Diaz-Araya, Guillermo ;
Lavandero, Sergio .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 2012, 1822 (04) :537-545
[8]   Role of Glycogen Synthase Kinase-3β in Cardioprotection [J].
Juhaszova, Magdalena ;
Zorov, Dmitry B. ;
Yaniv, Yael ;
Nuss, H. Bradley ;
Wang, Su ;
Sollott, Steven J. .
CIRCULATION RESEARCH, 2009, 104 (11) :1240-1252
[9]   Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury [J].
Lempiainen, Juha ;
Finckenberg, Piet ;
Mervaala, Elina E. ;
Storvik, Markus ;
Kaivola, Juha ;
Lindstedt, Ken ;
Levijoki, Jouko ;
Mervaala, Eero M. .
PHARMACOLOGY RESEARCH & PERSPECTIVES, 2014, 2 (03)
[10]   Deterioration of myocardial injury due to dexmedetomidine administration after myocardial ischaemia [J].
Mimuro, Soichiro ;
Katoh, Takasumi ;
Suzuki, Akira ;
Yu, Shuchun ;
Adachi, Yushi U. ;
Uraoka, Masahiro ;
Sano, Hideki ;
Sato, Shigehito .
RESUSCITATION, 2010, 81 (12) :1714-1717