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Bauhinia championii flavone inhibits apoptosis and autophagy via the PI3K/Akt pathway in myocardial ischemia/reperfusion injury in rats.

ABSTRACT: This study aimed to determine the effects of Bauhinia championii flavone (BCF) on myocardial ischemia/reperfusion injury (MI/RI) in rats and to explore potential mechanisms. The MI/RI model in rats was established by ligating the left anterior descending coronary artery for 30 minutes, then reperfusing for 3 hours. BCF at 20 mg/kg was given 20 minutes prior to ischemia via sublingual intravenous injection, with 24 ?g/kg phosphoinositide 3-kinase inhibitor (PI3K; wortmannin) as a control. The creatine kinase-MB and nitric oxide content were assessed by colorimetry. The levels of mitochondrial permeability transition pores and tumor necrosis factor alpha were determined by an enzyme-linked immunosorbent assay. Cardiomyocyte apoptosis was detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Additionally, the expression of PI3K, endothelial nitric oxide synthase, caspase-3, and Beclin1 was analyzed by fluorescence quantitative polymerase chain reaction and Western blotting, respectively. Akt and microtubule-associated protein 1 light chain 3-II protein levels were also evaluated. Pretreatment with BCF significantly decreased the levels of creatine kinase-MB, tumor necrosis factor alpha, and mitochondrial permeability transition pores, but increased the nitric oxide content. Furthermore, BCF inhibited apoptosis, downregulated caspase-3, Beclin1, and microtubule-associated protein 1 light chain 3-II, upregulated PI3K, and increased the protein levels of phosphorylated Akt and endothelial nitric oxide synthase. However, all of the previously mentioned effects of BCF were blocked when BCF was coadministered with wortmannin. In conclusion, these observations indicated that BCF has cardioprotective effects against MI/RI by reducing cell apoptosis and excessive autophagy, which might be related to the activation of the PI3K/Akt signaling pathway.

SUBMITTER: Jian J

PROVIDER: S-EPMC4642812 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Bauhinia championii flavone inhibits apoptosis and autophagy via the PI3K/Akt pathway in myocardial ischemia/reperfusion injury in rats.

Jian Jie J Xuan Feifei F Qin Feizhang F Huang Renbin R

Drug design, development and therapy 20151106

This study aimed to determine the effects of Bauhinia championii flavone (BCF) on myocardial ischemia/reperfusion injury (MI/RI) in rats and to explore potential mechanisms. The MI/RI model in rats was established by ligating the left anterior descending coronary artery for 30 minutes, then reperfusing for 3 hours. BCF at 20 mg/kg was given 20 minutes prior to ischemia via sublingual intravenous injection, with 24 μg/kg phosphoinositide 3-kinase inhibitor (PI3K; wortmannin) as a control. The cre ...[more]

PMID: 26604691

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Project description:Ischemia-reperfusion (I/R) could cause heart irreversible damage, which is tightly combined with glucose metabolism disorder. It is demonstrated that GLUT4 (glucose transporter 4) translocation is critical for glucose metabolism in the cardiomyocytes under I/R injury. Moreover, DRD4 (dopamine receptor D4) modulate glucose metabolism, and protect neurocytes from anoxia/reoxygenation (A/R) injury. Thus, DRD4 might regulate myocardial I/R injury in association with GLUT4-mediated glucose metabolism. However, the effects and mechanisms are largely unknown. In the present study, the effect of DRD4 in heart I/R injury were studied ex vivo and in vitro. For I/R injury ex vivo, DRD4 agonist (PD168077) was perfused by Langendorff system in the isolated rat heart. DRD4 activated by PD168077 improved cardiac function in the I/R-injured heart as determined by the left ventricular developed pressure (LVDP), +dp/dt, and left ventricular end diastolic pressure (LVEDP), and reduced heart damage evidenced by infarct size, the release of troponin T (TNT) and lactate dehydrogenase (LDH). DRD4 activation diminished I/R injury induced apoptosis and enhanced cell viability impaired by I/R injury in cardiomyocyte, showed by TUNEL staining, flow cytometer and CCK8 assay. Furthermore, DRD4 activation did not change total GULT4 protein expression level but increased the membrane GULT4 localization determined by western blot. In terms of mechanism, DRD4 activation increased pPI3K/p-AKT but not the total PI3K/AKT during anoxia/reoxygenation (A/R) injury in vitro. Interestingly, PI3K inhibitor, Wortmannin, blocked PI3K/AKT pathway and depleted the membrane GULT4, and further promoted apoptosis showed by TUNEL staining, flow cytometer, western blot of cleaved caspase 3, BAX and BCL2 expression. Thus, DRD4 activation exerted a protective effect against I/R injury by promoting GLUT4 translocation depended on PI3K/AKT pathway, which enhanced the ability of glucose uptake, and ultimately reduced the apoptosis in cardiomyocytes.

Project description:Long non‑coding RNAs (lncRNAs) have been revealed to have a marked effect in cardiovascular diseases, including during cardiac development, cardiac hypertrophy, myocardial fibrosis and myocardial ischemic injury. The mechanism of myocardial ischemia‑reperfusion injury (MIRI) is very complicated. Although studies have confirmed that lncRNAs are involved, the specific mechanism remains largely unknown. The lncRNA growth arrest specific 5 (GAS5) is known as a regulator of a number of diseases, including certain cancer types. The present study aimed to investigate the function of lncRNA GAS5 in MIRI. The present study reported that the expression of lncRNA GAS5 in H9c2 cells treated with anoxia and reoxygenation was significantly upregulated compared with the control group (P<0.05). Similarly, the expression of lncRNA GAS5 in myocardial tissue obtained from rats treated with MIRI was significantly upregulated compared with the untreated controls (P<0.05). Silencing of lncRNA GAS5 was able to attenuate myocardial damage, as cell viability increased and the apoptosis rate decreased. Classical apoptotic proteins involved in MIRI, including B‑cell lymphoma 2, Bcl‑2‑associated X protein and cleaved caspase‑3, also exhibited the same trend. At the same time, when lncRNA GAS5 was silenced, microRNA (miR)‑532‑5p, which was originally expressed at the stage of injury, was upregulated. The luciferase reporter assay results indicated that the lncRNA GAS5 functioned as a molecular sponge of miR‑532‑5p. The gain‑ and loss‑of‑function analysis of miR‑532‑5p indicated that it was involved in the regulation of MIRI; the trend of results following its overexpression was also consistent with the trend observed following the silencing of lncRNA GAS5. Notably, the protective effect of lncRNA GAS5 silencing on cells was attenuated by miR‑532‑5p inhibition. Phosphatase and tensin homolog was revealed to be a key target gene for the function of lncRNA GAS5, and its regulation was achieved via binding to miR‑532‑5p. In other words, silencing lncRNA GAS5 ultimately promoted the activation of the phosphoinositide‑3‑kinase (PI3K)/protein kinase B pathway (AKT) to reduce myocardial damage. Therefore, lncRNA GAS5 was able to regulate MIRI through the PI3K/AKT apoptosis pathway by sponging miR‑532‑5p.

Project description:BackgroundIschemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism.MethodsCornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood-brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells.ResultsThe results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood-brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5-10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells.ConclusionsThese results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

Project description:Reperfusion therapy after myocardial infarction may lead to myocardial injury, which can be complicated and exacerbated by diabetes. The existing therapeutic methods for myocardial ischemia-reperfusion injury (MIRI) in diabetic patients are not ideal. Oleoylethanolamide (OEA) has been found to have protective effects on diabetes and acute cerebral ischemia. This study aimed to determine whether OEA can alleviate MIRI in diabetic rats, and to explore the underlying mechanism. The model of diabetic rats with MIRI was established by blocking the left coronary artery for 30 min, followed by restoring blood flow stability for 120 min. The myocardial enzyme spectrum, area of MIRI, and expression levels of apoptosis-related proteins were detected. The results showed that OEA pretreatment could reduce myocardial infarction area, protect myocardial tissue structure, and reduce myocardial cell apoptosis in diabetic rats with MIRI. Meanwhile, the levels of creatine kinase (CK)-MB (CK-MB), lactate dehydrogenase (LDH), and malondialdehyde (MDA) were reduced, while superoxide dismutase (SOD) level was elevated. H9C2 cells were treated with high glucose and oxygen-glucose deprivation/reperfusion (OGD/R) to establish an in vitro model. Capsazepine (CPZ), an antagonist of transient receptor potential vanilloid subtype 1 (TRPV1), and LY294002, an inhibitor of PI3K, were used to treat H9C2 cells in vitro. Apoptosis level and the expression levels of apoptosis-related proteins were measured. It was found that OEA activated TRPV1 and the PI3K/Akt signaling pathway, downregulated the expression levels of apoptosis-related proteins (Bcl-2 and cleaved caspase-3), and ameliorated the apoptosis of H9C2 cells treated with high glucose and OGD/R. This study clarified that OEA, as a TRPV1 agonist, could reduce myocardial cell apoptosis by activating the PI3K/Akt signaling pathway in diabetic rats with MIRI. The findings may provide a theoretical basis for administration of OEA as a potential therapeutic agent into diabetic patients with MIRI.

Dataset Information

Bauhinia championii flavone inhibits apoptosis and autophagy via the PI3K/Akt pathway in myocardial ischemia/reperfusion injury in rats.

Publications

Bauhinia championii flavone inhibits apoptosis and autophagy via the PI3K/Akt pathway in myocardial ischemia/reperfusion injury in rats.

Similar Datasets

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