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Effect of WDR26on the Opening of Mitochondrial Permeability Transition Pore (MPTP) of Cardiomyocytes Induced by Oxidative Stress and Its Myocardial Protective Role

Author: FengYanSheng
Tutor: XiaoXianZhong
School: Central South University
Course: Pathology and Pathophysiology
Keywords: myocardial ischemia-reperfusion injury WDR26 apoptosis mitochondrial permeability transition pore oxidative stress myocardial protection cardiomyocyte VDAC ANT
CLC: R363
Type: PhD thesis
Year: 2012
Downloads: 269
Quote: 0
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Abstract


Myocardial ischemia-reperfusion injury is the myocardial damage caused when blood is re-supplied to the tissue after a period of ischemia, which usually occurs in coronary artery bypass grafting, cardiovascular embolism reperfusion and cardio-pulmonary resuscitation after extraco-rporeal circulation. There are a few mechanisms related to myocardial ischemia-reperfusion injury:the generation of reactive oxygen species, calcium overload, micro vascular damage and energy metabolism disorder. Reactive oxygen species such as hydrogen peroxide, oxygen ions and oxygen free radicals play an important role in myocardial ischemia-reperfusion injury.The WD40repeat (also known as beta-transducin repeat or the WD) is a small structural motif with almost40amino acids, typically bracketed by gly-his and trp-asp (GH-WD). Several of these repeats are combined to form a type of protein domain called the WD domain. WD-containing proteins have4to16repeating units, all of which are thought to form a beta-propeller structure. The importance of these proteins is not only demonstrated by their critical roles in many essential biological functions such as signal transduction, transcription regulation and apoptosis, but also recognized by their association with several human diseases. The important functions of all WD-repeat proteins are accomplished via forming multi-protein complex assemblies, where the repeating units serve as a rigid scaffold for protein interactions. WDR26, as a novel protein of the WD40repeats, was first identified in our lab. WDR26is up-regulated during ischemic preconditioning (IPC), so is also called myocardial ischemic preconditioning up-regulated protein2(Mipu2). Although it is a protein up-regulated during ischemic preconditioning, its role in myocardial ischemia reperfusion injury is still unclear.To observe the expression pattern of WDR26, we used the models of rat myocardial ischemia-reperfusion injury was applied and cell injury was induced by hydrogen peroxide. Real-time PCR and Western blot were performed to determine the expression of WDR26in mRNA and protein levels. Our results showed that WDR26was increased significantly in both mRNA and protein in myocardial ischemia-reperfusion injury and oxidative stress injuried cells.To determine the subcellular localization of WDR26, We analyzed the cell fractions from rat cardiac and H9c2cardiac myoblast cells by Western blot. Analysis of mitochondrial fractions showed that WDR26was localized in the mitochondria. To confirm these biochemical data, immunofluorescence for WDR26and a marker that selectively staining mitochondria (MitoTracker Red dye) was performed in H9c2cells. Merging of the signals by confocal microscopy supported the localization of WDR26in the mitochondria.To determine the role of WDR26in myocardial injury, we overexpressed and inhibited the expression of WDR26in H9c2cells. The results showed that WDR26could prevent oxidative stress-induced apoptosis and cell injury. Overexpression of WDR26also inhibited H2O2-induced activation of Caspase3and Caspase9and reduced the release of cytochrome c from mitochondria. These results indicated that WDR26could inhibit the cardiomyocytes injury and apoptosis induced by hydrogen peroxide, potentially through mitochondrial cell death pathway.The biological function of WD-repeat proteins is achieved through interacting with other proteins. We screened WDR26interacting protein by immunoprecipitation and protein mass spectrometry. We firstly found WDR26can interact with50proteins. According to the anti-apoptotic role of WDR26demonstrated previously, we further investigated and demonstrated that WDR26could interact with voltage-dependent anion channel protein (VDAC) and adenine nucleotide translocator (ANT). To detect its role in mitochondrial permeability transition pore, we examined the transmembrane potential of mitochondria and mitochondrial swelling. The results showed that overexpression of WDR26prohibited the decrease of transmembrane potential of mitochondria and mitochondrial swelling induced by hydrogen peroxide.Taken together, as a novel protein, WDR26plays important protective effects on myocardial ischemia-reperfusion injury. WDR26can be induced by myocardial ischemia-reperfusion injury and oxidative stress. WDR26is localized at mitochondria. WDR26overexpression can inhibit H2O2-induced LDH release, the decrease in cell viability and apoptosis by the interaction with VDAC and ANT and inhibition of the opening of mitochondrial permeability transition pore (mPTP).These findings reveal the role of WDR26in myocardial protection; from the perspective of protein interaction, we firstly reveal the molecular mechanism of WDR26myocardial protective role.

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