Propofol induces mitochondrial-associated protein LRPPRC and protects mitochondria against hypoxia in cardiac cells

Abstract

Background Hypoxia-induced oxidative stress is one of the main mechanisms of myocardial injury, which frequently results in cardiomyocyte death and precipitates life-threatening heart failure. Propofol (2,6-diisopropylphenol), which is used to sedate patients during surgery, was shown to strongly affect the regulation of physiological processes, including hypoxia-induced oxidative stress. However, the exact mechanism is still unclear. Methods Expression of LRPPRC, SLIRP, and Bcl-2 after propofol treatment was measured by RT-qPCR and western blot analyses. The effects of propofol under hypoxia were determine by assessing mitochondrial homeostasis and mitochondrial function, including the ATP level and mitochondrial mass. Autophagy/mitophagy was measured by detecting the presence of LC3B, and autophagosomes were observed by transmission microscopy Results Propofol treatment inhibited cleaved caspase-9 and caspase-3, indicating its inhibitory roles in mitochondrial-related apoptosis. Propofol treatment also transcriptionally activated LRPPRC, a mitochondrial-associated protein that exerts multiple functions by maintaining mitochondrial homeostasis, in a manner dependent on the presence of hypoxia-induced factor (HIF)-1α transcriptional activity in H9C2 and primary rat cardiomyocytes. LRPPRC induced by propofol maintained the mitochondrial membrane potential (MMP) and promoted mitochondrial function, including ATP synthesis and transcriptional activity. Furthermore, LRPPRC induced by propofol contributes, at least partially, to the inhibition of apoptotic cell death induced by hypoxia.

Propofol via Antioxidant Property Attenuated Hypoxia-Mediated Mitochondrial Dynamic Imbalance and Malfunction in Primary Rat Hippocampal Neurons

“…Although Fis1 was also reported to play a role in mitochondrial fission [ 33 ], we found it was not affected by hypoxia ( Figure 5(a) ). In addition, we reported in hippocampal neurons hypoxia-induced Drp1 expression was due to hypoxia-sensitive transcription factor HIF-1 α ( Figure 6(a) ), which was consistent with previous publications carried out in fibroblasts [ 30 ], cardiac cells [ 22 ], and vascular smooth muscle cells [ 34 ]. Although other transcription factors such as Smad2/3 [ 35 ], NF- κ B [ 36 ], and calcium-related transcription factors [ 37 ] have been reported to correlate with Drp1 expression, we demonstrated that HIF-1 α inhibitors could almost completely inhibit hypoxia-induced Drp1 expression ( Figure 6(b) ), and thus, suggesting the pivotal role of HIF-1 α .…”

“…also reported to play a role in mitochondrial fission [33], we found it was not affected by hypoxia (Figure 5(a)). In addition, we reported in hippocampal neurons hypoxiainduced Drp1 expression was due to hypoxia-sensitive transcription factor HIF-1α (Figure 6(a)), which was consistent with previous publications carried out in fibroblasts [30], cardiac cells [22], and vascular smooth muscle cells [34].…”

“…In this study, hippocampal neuron viability was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay as described previously [ 22 ]. MTT is a dye that could interact with succinate dehydrogenase in the mitochondria of living cells, forming insoluble formazan crystals.…”

“…And it was revealed that short-term application of propofol showed no harm to mitochondria and should be safe even in mitochondrial disorder models [ 21 ]. Importantly, a recent study indicated propofol may reduce oxidative stress and protect mitochondria in hypoxia-treated cardiac cells [ 22 ]. Also, an in vitro study carried out in hippocampal neurons demonstrated propofol could alleviate ischemia-reperfusion- (I/R-) induced MMP loss and thus protect hippocampal neurons from I/R injury [ 23 ].…”

LRPPRC regulates metastasis and glycolysis by modulating autophagy and the ROS/HIF1-α pathway in retinoblastoma

“… 31 , 32 , 33 In addition, LRPPRC could regulate mitochondrial homeostasis through targeting HIF1-α. 34 Therefore, LRPPRC might regulate the ROS/HIF1-α pathway through affecting autophagy and further influence mitochondrion function. Knockdown of LRPPRC slightly upregulated the expression of ROS/HIF1-α, but treatment with the lysosomal inhibitor suppressed the level of ROS/HIF1-α, indicating LRPPRC could activate the ROS/HIF1-α pathway via suppressing autophagy.…”