Apoptotic signaling induces hyperpermeability following hemorrhagic shock

2007 ◽  
Vol 292 (6) ◽  
pp. H3179-H3189 ◽  
Author(s):  
Ed W. Childs ◽  
Binu Tharakan ◽  
Felicia A. Hunter ◽  
John H. Tinsley ◽  
Xiaobo Cao
Keyword(s):  
Cytochrome C ◽  
Hemorrhagic Shock ◽  
Caspase 3 ◽  
Mitochondrial Cytochrome ◽  
Intrinsic Apoptotic Pathway ◽  
Intrinsic Pathway ◽  
Apoptotic Pathway ◽  
Apoptotic Signaling ◽  
Mitochondrial Cytochrome C

Hemorrhagic shock (HS) disrupts the endothelial cell barrier, resulting in microvascular hyperpermeability. Recent studies have also demonstrated that activation of the apoptotic signaling cascade is involved in endothelial dysfunction, which may result in hyperpermeability. Here we report involvement of the mitochondrial “intrinsic” pathway in microvascular hyperpermeability following HS in rats. HS resulted in the activation of the mitochondrial intrinsic pathway, as is evident from an increase in the proapoptotic Bcl-2 family member BAK, release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. This, along with the in vivo transfection of the proapoptotic peptide BAK (BH3), resulted in hyperpermeability (as visualized by intravital microscopy), release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. Conversely, transfection of the BAK (BH3) mutant had no effect on hyperpermeability. Together, these results demonstrate involvement of the mitochondrial intrinsic apoptotic pathway in HS-induced hyperpermeability and that the attenuation of this pathway may provide an alternative strategy in preserving vascular barrier integrity.

Platycodon grandiflorum Induces Apoptosis in SKOV3 Human Ovarian Cancer Cells Through Mitochondrial-Dependent Pathway

2010 ◽  
Vol 38 (02) ◽  
pp. 373-386 ◽  
Author(s):  
Qin Hu ◽  
Ruile Pan ◽  
Liwei Wang ◽  
Bo Peng ◽  
Jingtian Tang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Ovarian Cancer Cells ◽  
Mitochondrial Cytochrome ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Platycodon Grandiflorum ◽  
Mitochondrial Cytochrome C

Platycodon grandiflorum (Jacq.) A. DC., a Chinese food and medicine, has been used as expectorant traditionally. The present study aimed to investigate the effect of Platycodon grandiflorum extract (PGE) on SKOV3 ovarian cancer cells. 3-(4,5- dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay was used to monitor cell numbers, Annexin-V/propidium iodide (PI) staining, RT-PCR and Western blot were used to examine cell apoptosis, caspases activation. Bcl-2 and Bax expressions and mitochondrial cytochrome c release. Our result showed that PGE-induced apoptosis was associated with activation of caspase-3, -8 and -9, down-regulation of Bcl-2, up-regulation of Bax and release of mitochondrial cytochrome c to cytosol. The data indicate that PGE may have anti-tumor effect mainly via caspase-3 and caspase-9 dependent apoptotic pathway.

Angiopoietin-1 inhibits intrinsic apoptotic signaling and vascular hyperpermeability following hemorrhagic shock

2008 ◽  
Vol 294 (5) ◽  
pp. H2285-H2295 ◽  
Author(s):  
Ed W. Childs ◽  
Binu Tharakan ◽  
Nickolas Byrge ◽  
John H. Tinsley ◽  
Felicia A. Hunter ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Hemorrhagic Shock ◽  
Caspase 3 ◽  
Microvascular Endothelial Cell ◽  
Cytochrome C Release ◽  
Apoptotic Signaling ◽  
Microvascular Endothelial ◽  
Lung Microvascular Endothelial Cell ◽  
Angiopoietin 1

Studies from our laboratory demonstrated the involvement of intrinsic apoptotic signaling in hyperpermeability following hemorrhagic shock (HS). Angiopoietin 1 (Ang-1), a potent inhibitor of hyperpermeability, was recently shown to inhibit apoptosis. The purpose of our study was to determine the effectiveness of Ang-1 in attenuating HS-induced hyperpermeability and its relationship to apoptotic signaling. HS was induced in rats by withdrawing blood to reduce the mean arterial pressure to 40 mmHg for 1 h, followed by reperfusion. Mesenteric postcapillary venules were examined for changes in hyperpermeability by intravital microscopy. Mitochondrial release of second mitochondrial derived activator of caspases (smac) and cytochrome c were determined by Western blot and ELISA, respectively. Caspase-3 activity was determined by fluorometric assay. Parallel studies were performed in rat lung microvascular endothelial cell (RLMEC) monolayers, utilizing HS serum and the proapoptotic Bcl-2 homologous antagonist/killer [BAK (BH3)] peptide as inducers of hyperpermeability. In rats, Ang-1 (200 ng/ml) attenuated HS-induced hyperpermeability versus the HS group ( P < 0.05). Ang-1 prevented HS-induced collapse of mitochondrial transmembrane potential (ΔΨm), smac and cytochrome c release, and caspase-3 activity ( P < 0.05). In RLMEC monolayers, HS serum and BAK (BH3) peptide both induced hyperpermeability that was inhibited by Ang-1 ( P < 0.05). Ang-1 attenuated HS and BAK (BH3) peptide-induced collapse of ΔΨm, smac release, cytochrome c release, activation of caspase-3, and vascular hyperpermeability. In vivo, BAK (BH3) induced vascular hyperpermeability that was attenuated by Ang-1 ( P < 0.05). These findings suggest that Ang-1's role in maintaining microvascular endothelial barrier integrity involves the intrinsic apoptotic signaling cascade.

Cytochrome c release into cytosol with subsequent caspase activation during warm ischemia in rat liver

2001 ◽  
Vol 281 (4) ◽  
pp. G1115-G1123 ◽  
Author(s):  
Junpei Soeda ◽  
Shinichi Miyagawa ◽  
Kenji Sano ◽  
Junya Masumoto ◽  
Shun'Ichiro Taniguchi ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Dna Fragmentation ◽  
Warm Ischemia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Dependent Manner ◽  
Mitochondrial Cytochrome ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Mitochondrial Cytochrome C

Apoptosis plays an important role in liver ischemia and reperfusion (I/R) injury. However, the molecular basis of apoptosis in I/R injury is poorly understood. The aims of this study were to ascertain when and how apoptotic signal transduction occurs in I/R injury. The apoptotic pathway in rats undergoing 90 min of warm ischemia with reperfusion was compared with that of rats undergoing prolonged ischemia alone. During ischemia, mitochondrial cytochrome c was released into the cytosol in a time-dependent manner in hepatocytes and sinusoidal endothelial cells, and caspase-3 and an inhibitor of caspase-activated DNase were cleaved. However, apoptotic manifestation and DNA fragmentation were not observed. After reperfusion, nuclear condensation, cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, and DNA fragmentation were observed and caspase-8 and Bid cleavage occurred. In contrast, prolonged ischemia alone induced necrosis rather than apoptosis. In summary, our results show that release of mitochondrial cytochrome c and caspase activation proceed during ischemia, although apoptosis is manifested after reperfusion.

scholarly journals Upregulation of UCP2 Expression Protects against LPS-Induced Oxidative Stress and Apoptosis in Cardiomyocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Jinda Huang ◽  
Wanwan Peng ◽  
Yijun Zheng ◽  
Hu Hao ◽  
Sitao Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Protein Level ◽  
Caspase 3 ◽  
Uncoupling Protein ◽  
Dependent Manner ◽  
Mitochondrial Cytochrome ◽  
Protein Levels ◽  
Ucp2 Expression ◽  
Mitochondrial Cytochrome C

Uncoupling protein 2 (UCP2) has a cardioprotective role under septic conditions, but the underlying mechanism remains unclear. This study aimed at investigating the effects of UCP2 on the oxidative stress and apoptosis of cardiomyocytes induced by lipopolysaccharide (LPS). First, LPS increased UCP2 expression in cardiomyocytes in a time-dependent manner. LPS increased the production of lactate dehydrogenase (LDH), reactive oxygen species (ROS), and malondialdehyde (MDA) and decreased the level of superoxide dismutase (SOD). However, UCP2 knockdown increased the LPS-induced cardiac injury and oxidative stress. In addition, LPS damaged the mitochondrial ultrastructure and led to the disruption of mitochondrial membrane potential (MMP), as well as the release of mitochondrial cytochrome c. UCP2 knockdown aggravated mitochondrial injury and the release of mitochondrial cytochrome c. LPS increased the protein levels of Bax and cleaved-caspase-3, decreased the protein level of Bcl-2, and upregulated the protein level of mitogen-activated protein kinase. However, upon UCP2 knockdown, the protein levels of Bax and cleaved-caspase-3 increased even further, and the protein level of Bcl-2 was further decreased. The protein level of phosphorylated p38 was also further enhanced. Thus, UCP2 protects against LPS-induced oxidative stress and apoptosis in cardiomyocytes.

scholarly journals Saussurea lappa Exhibits Anti-Oncogenic Effect in Hepatocellular Carcinoma, HepG2 Cancer Cell Line by Bcl-2 Mediated Apoptotic Pathway and Mitochondrial Cytochrome C Release

2021 ◽  
Vol 43 (2) ◽  
pp. 1114-1132
Author(s):  
Amal A. Alotaibi ◽  
Asmatanzeem Bepari ◽  
Rasha Assad Assiri ◽  
Shaik Kalimulla Niazi ◽  
Sreenivasa Nayaka ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Cancer Cell ◽  
Mitochondrial Cytochrome ◽  
Cytochrome C Release ◽  
Apoptotic Pathway ◽  
Important Species ◽  
Saussurea Lappa ◽  
Butanol Extract ◽  
Mitochondrial Cytochrome C

Background and Objectives: Saussurea lappa (S. lappa) is an important species of the Asteraceae family with several purposes in traditional medicine. This study intended to explore the cytotoxic effect of S. lappa on HepG2 cancer cell proliferation. Materials and Methods: The effects of an S. lappa n-butanol extract on the induction of apoptosis were investigated by flow cytometry and mitochondrial cytochrome C-releasing apoptosis assay. Additionally, real-time PCR was employed to confirm apoptosis initiation. Further, qualitative estimation of the active constituent of S. lappa was done by gas chromatography–mass spectroscopy (GC–MS). Results: The cell viability study revealed that the n-butanol extract of S. lappa demonstrated potent cytotoxicity against HepG2 cancer cells, with an IC50 value of 56.76 μg/mL. Cell morphology with dual staining of acridine orange (AO)-ethidium bromide (EB) showed an increase in orange/red nuclei due to cell death by S. lappa n-butanol extract compared to control cells. Apoptosis, as the mode of cell death, was also confirmed by the higher release of cytochrome C from mitochondria, the increased expression of caspase-3 and bax, along with down regulation of Bcl-2. Conclusion: These findings conclude that S. lappa is a cause of hepatic cancer cell death through apoptosis and a potential natural source suggesting furthermore investigation of its active compounds that are responsible for these observed activities.

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