taurochenodeoxycholic-acid and Hypoxia

Obstructive sleep apnea (OSA) is associated with pulmonary fibrosis and endothelial apoptosis in pulmonary tissues. Chronic intermittent hypoxia (IH) is considered to be the primary player in OSA, but the mechanisms underlying its effect on pulmonary tissues are unknown. Endoplasmic reticulum (ER) stress induced by IH treatment plays an important role in accelerating the process of fibrosis and induction of apoptosis.. After 4 weeks of IH treatment, the expressions of two ER stress markers, glucose regulated protein-78 (Grp78) and transcription factor C/EBP homologous protein (CHOP) were increased which was prevented by administration of the ER stress attenuator, TUDCA. The expressions of PERK, but not those of ATF-6 and IRE-1, were increased. The effects of IH were accompanied by an increased number of apoptotic cells and increased expressions of cleaved caspase-3 and caspase-12 in pulmonary tissues. In addition, histological examination suggested the presence of fibrosis after chronic IH treatment, indicated by increased expression of collagen, which was associated with the up-regulation of TGF-β1 and TSP-1 that are known to promote fibrosis. Similarly, TUDCA could reduce the extent of fibrotic area and the expression levels of these proteins.. It reveals the roles of ER stress, especially the PERK pathway, in IH induced apoptosis and fibrosis in pulmonary tissues that might underlie the pulmonary complications observed in OSA.

Topics: Animals; Apoptosis; Caspase 12; Caspase 3; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fibrosis; Hypoxia; Lung; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Taurochenodeoxycholic Acid; Transcription Factor CHOP

This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits.. Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA.. These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment.

Topics: Animals; Caspase 3; Endoplasmic Reticulum Stress; Hippocampus; Hypoxia; Male; Memory; Memory, Long-Term; Mice, Inbred C57BL; Mitochondria; Neuronal Plasticity; Neurons; Phenylbutyrates; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Spine; Taurochenodeoxycholic Acid

To explore the mechanism of tauroursodeoxycholic acid (TUDCA) in suppressing apoptosis in pulmonary tissues of intermittent hypoxia (IH) mice model.
. A total of 32 C57 mice were randomly divided into a control group, a TUDCA group, an IH group and an IH+TUDCA group (8 mice per group). The mice were put in specially designed chambers and exposed to IH treatment for 4 weeks. In the chambers, oxygen levels repeatedly decreased from 21% to 10% and recovered from 10% to 21%, lasting for 8 hours in every day. After 4 weeks of IH exposure, the expression levels of caspase-12 and cleaved caspase-3 in pulmonary tissues were detected by Western blot. Meanwhile, the expression levels of glucose regulated protein-78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) were quantified by Western blot, immunochemistry and real-time PCR.
. Compared with the control group, the expression levels of caspase-12, cleaved caspase-3, GRP78 and CHOP were increased in the IH group (all P<0.01). TUDCA treatment could reduce these proteins expression (all P<0.05).
. Endoplasmic reticulum stress-mediated apoptosis can be activated in pulmonary tissues after chronic IH exposure, and TUDCA can reduce the cellular apoptosis via suppressing endoplasmic reticulum stress.. 目的：探究牛磺熊去氧胆酸钠(tauroursodeoxycholic acid sodium，TUDCA)在间歇性低氧(intermittent hypoxia，IH)模型小鼠肺组织中抑制细胞凋亡的机制。方法：32只C57小鼠随机分为对照组、TUDCA组、IH组和IH+TUDCA组，每组8只。将C57小鼠放入低氧舱中进行IH处理4周 (氧气浓度从21%下降到10%，再从10%恢复到21%为一个循环，每个循环的时间为90 s)，每天持续8 h。4周IH处理后，Western印迹检测caspase-12和cleaved caspase-3在肺组织中的表达。同时，Western印迹、免疫组织化学和实时定量PCR检测葡萄糖调节蛋白78(glucose regulated protein 78，GRP78) 和CCAAT/增强结合蛋白同源蛋白(CCAAT/enhancer-binding protein homologous protein，CHOP)的表达。结果：与对照组和TUDCA组相比，IH组小鼠肺组织中caspase-12，cleaved caspase-3，GRP78和CHOP表达明显升高(均P<0.01)；而在IH+TUDCA组中，TUDCA能够显著地减少上述蛋白的表达(均P<0.05)。结论：慢性的IH能够导致肺组织中内质网应激介导的细胞凋亡，而TUDCA可以通过抑制内质网应激的激活来降低细胞的凋亡水平。.

Topics: Animals; Apoptosis; Caspase 12; Caspase 3; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hypoxia; Lung; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Taurochenodeoxycholic Acid; Transcription Factor CHOP

Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries of patients with pulmonary arterial hypertension has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with pulmonary arterial hypertension like hypoxia, inflammation, or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of activating transcription factor 6, which, via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in pulmonary arterial hypertension that promotes proliferation and apoptosis resistance in the pulmonary artery wall. We hypothesized that chemical chaperones known to suppress ER stress signaling, like 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension.. PBA in the drinking water both prevented and reversed chronic hypoxia-induced pulmonary hypertension in mice, decreasing pulmonary vascular resistance, pulmonary artery remodeling, and right ventricular hypertrophy and improving functional capacity without affecting systemic hemodynamics. These results were replicated in the monocrotaline rat model. PBA and tauroursodeoxycholic acid improved ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation (cleavage, nuclear localization, luciferase, and downstream target expression), and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. In addition, these chemical chaperones suppressed proliferation and induced apoptosis in pulmonary artery smooth muscle cells in vitro and in vivo.. Attenuating ER stress with clinically used chemical chaperones may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.

Topics: Activating Transcription Factor 6; Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cholagogues and Choleretics; Chronic Disease; Disease Models, Animal; Endoplasmic Reticulum Stress; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Inbred C57BL; Mitochondria; Models, Cardiovascular; Phenylbutyrates; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Signal Transduction; Taurochenodeoxycholic Acid