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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)-1? 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. CONCLUSION:Taken together, our results indicate that LRPPRC may have a protective antioxidant effect by maintaining mitochondrial homoeostasis induced by propofol and provide new insight into the protective mechanism of propofol against oxidative stress.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC7478836 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Zhang Qianlu Q Cai Shiwei S Guo Liping L Zhao Guojun G

PloS one 20200908 9

<h4>Background</h4>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.<h4>Methods</h4>Expression of LRPPRC, SLIRP, and Bcl-2 ...[more]

PMID: 32898195

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Project description:BackgroundMitochondrial dysfunction would ultimately lead to myocardial cell apoptosis and death during ischemia-reperfusion injuries. Autophagy could ameliorate mitochondrial dysfunction by autophagosome forming, which is a catabolic process to preserve the mitochondrial's structural and functional integrity. HO-1 induction and expression are important protective mechanisms. This study in order to investigate the role of HO-1 during mitochondrial damage and its mechanism.Methods and resultsThe H9c2 cardiomyocyte cell line were incubated by hypoxic and then reoxygenated for the indicated time (2, 6, 12, 18, and 24 h). Cell viability was tested with CCK-8 kit. The expression of endogenous HO-1(RT-PCR and Western blot) increased with the duration of reoxygenation and reached maximum levels after 2 hours of H/R; thereafter, the expression gradually decreased to a stable level. Mitochondrial dysfunction (Flow cytometry quantified the ROS generation and JC-1 staining) and autophagy (The Confocal microscopy measured the autophagy. RFP-GFP-LC3 double-labeled adenovirus was used for testing.) were induced after 6 hours of H/R. Then, genetic engineering technology was employed to construct an Lv-HO1-H9c2 cell line. When HO-1 was overexpressed, the LC3II levels were significantly increased after reoxygenation, p62 protein expression was significantly decreased, the level of autophagy was unchanged, the mitochondrial membrane potential was significantly increased, and the mitochondrial ROS level was significantly decreased. Furthermore, when the HO-1 inhibitor ZnPP was applied the level of autophagy after reoxygenation was significantly inhibited, and no significant improvement in mitochondrial dysfunction was observed.ConclusionsDuring myocardial hypoxia-reoxygenation injury, HO-1 overexpression induces autophagy to protect the stability of the mitochondrial membrane and reduce the amount of mitochondrial oxidation products, thereby exerting a protective effect.

Project description:BackgroundLeucine-rich pentatricopeptide repeat containing (LRPPRC) is a potential oncogene in multiple tumor types, including lung adenocarcinoma, esophageal squamous cell carcinoma and gastric cancer. LRPPRC exerts its tumor-promoting effects mainly by regulating mitochondrial homeostasis and inducing oxidative stress. However, the exact role and mechanisms by which LRPPRC acts in osteosarcoma and osteosarcoma-derived cancer stem-like cells (CSCs), which potentially critically contribute to recurrence, metastasis and chemoresistance, are still largely unclear.MethodsLRPPRC level in osteosarcoma cells and CSCs were detected by western blot. Effects of LRPPRC on CSCs were accessed after LRPPRC knockdown by introducing lentivirus containing shRNA targeting to LRPPRC mRNA.Resultswe found that LRPPRC was highly expressed in several osteosarcoma cell lines and that LRPPRC knockdown inhibited malignant behaviors, including proliferation, invasion, colony formation and tumor formation, in MG63 and U2OS cells. Enriched CSCs derived from MG63 and U2OS cells presented upregulated LRPPRC levels compared to parental cells (PCs), and LRPPRC knockdown markedly decreased the sphere-forming capacity. These findings demonstrate that LRPPRC knockdown decreased stemness in CSCs. Consistent with a previous report, LRPPRC knockdown decreased the expression levels of FOXM1 and its downstream target genes, including PRDX3, MnSOD and catalase, which are responsible for scavenging reactive oxygen species (ROS). Expectedly, LRPPRC knockdown increased the accumulation of ROS in osteosarcoma and osteosarcoma-derived CSCs under hypoxic conditions due to the decrease in ROS scavenging proteins. Moreover, LRPPRC knockdown sensitized osteosarcomas and CSCs against carboplatin, a ROS-inducing chemoagent, and promoted apoptosis. Furthermore, LRPPRC knockdown significantly decreased the mitochondrial membrane potential, disturbed mitochondrial homeostasis and led to mitochondrial dysfunction.ConclusionTaken together, these findings indicated that LRPPRC exerts critical roles in regulating mitochondrial homeostasis, mitochondrial function and tumorigenesis in osteosarcomas and osteosarcoma-derived CSCs. This suggests that LRPPRC might be a promising therapeutic target for osteosarcomas.

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

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

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