Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

Koyama, Masayuki; Furuhashi, Masato; Ishimura, Shutaro; Mita, Tomohiro; Fuseya, Takahiro; Okazaki, Yusuke; Yoshida, Hiroyuki; Tsuchihashi, Kazufumi; Miura, Tetsuji

doi:10.1152/ajpheart.00869.2013

Cited by 81 publications

(62 citation statements)

References 38 publications

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“…21) and an increase in arterial BP (6,35,57,62). As ER stress inhibitors have been shown to prevent both ANG II-induced systemic hypertension (37) and hypoxiainduced pulmonary arterial hypertension (42) in mice, our data suggest that prolonged ER stress induced by IH could contribute to the IH-induced elevation of arterial BP. We further confirmed that chronic exposure to IH was associated with an increased response to myocardial ischemia-reperfusion (i.e., increased infarct size), which is consistent with previous studies in both rodents (6,35,54,57,62) and humans (9).…”

Section: Ih-induced Increase In Bp and Infarct Size: Potential Role Omentioning

confidence: 61%

High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size

Bourdier

Flore

Sanchez³

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic intermittent hypoxia (IH) is described as the major detrimental factor leading to cardiovascular morbimortality in obstructive sleep apnea (OSA) patients. OSA patients exhibit increased infarct size after a myocardial event, and previous animal studies have shown that chronic IH could be the main mechanism. Endoplasmic reticulum (ER) stress plays a major role in the pathophysiology of cardiovascular disease. High-intensity training (HIT) exerts beneficial effects on the cardiovascular system. Thus, we hypothesized that HIT could prevent IH-induced ER stress and the increase in infarct size. Male Wistar rats were exposed to 21 days of IH (21-5% fraction of inspired O2, 60-s cycle, 8 h/day) or normoxia. After 1 wk of IH alone, rats were submitted daily to both IH and HIT (2 ϫ 24 min, 15-30m/min). Rat hearts were either rapidly frozen to evaluate ER stress by Western blot analysis or submitted to an ischemia-reperfusion protocol ex vivo (30 min of global ischemia/ 120 min of reperfusion). IH induced cardiac proapoptotic ER stress, characterized by increased expression of glucose-regulated protein kinase 78, phosphorylated protein kinase-like ER kinase, activating transcription factor 4, and C/EBP homologous protein. IH-induced myocardial apoptosis was confirmed by increased expression of cleaved caspase-3. These IH-associated proapoptotic alterations were associated with a significant increase in infarct size (35.4 Ϯ 3.2% vs. 22.7 Ϯ 1.7% of ventricles in IH ϩ sedenary and normoxia ϩ sedentary groups, respectively, P Ͻ 0.05). HIT prevented both the IH-induced proapoptotic ER stress and increased myocardial infarct size (28.8 Ϯ 3.9% and 21.0 Ϯ 5.1% in IH ϩ HIT and normoxia ϩ HIT groups, respectively, P ϭ 0.28). In conclusion, these findings suggest that HIT could represent a preventive strategy to limit IHinduced myocardial ischemia-reperfusion damages in OSA patients.obstructive sleep apnea; intermittent hypoxia; ischemia-reperfusion; high-intensity aerobic training; endoplasmic reticulum stress NEW & NOTEWORTHYWe demonstrated that intermittent hypoxia induced cardiac proapoptotic ER stress and increased infarct size, which were prevented by high-intensity aerobic training. These results strengthen the need for early identification of patients with sleep apnea at risk for cardiovascular complications and suggest that exercise can be used as a new preventive strategy for these patients.

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Section: Ih-induced Increase In Bp and Infarct Size: Potential Role Omentioning

confidence: 61%

High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size

Bourdier

Flore

Sanchez³

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…Chemical chaperones are known to reduce ER-stress by facilitating protein folding and accelerating ER protein trafficking (57). Previous studies have shown that 4-PBA and TUDCA, two chemical chaperons, were able to inhibit ER-stress associated gene expression including CHOP and cell apoptotic death initiated by various stimuli (29,(58)(59)(60)(61). We therefore pretreated cells with either 4-PBA or TUDA at various doses to test if they inhibit NSC-induced ER-stress and cell death.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells

Wang

Zhao

et al. 2016

International Journal of Oncology

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Abstract. Castration-resistant prostate cancer (CRPC) is a major cause of prostate cancer (Pca) death. Chemotherapy is able to improve the survival of CRPC patients. We previously found that NSC606985 (NSC), a highly water-soluble camptothecin analog, induced cell death in Pca cells via interaction with topoisomerase 1 and activation of the mitochondrial apoptotic pathway. To further elucidate the role of NSC, we studied the effect of NSC on ER-stress and its association with NSC-induced cell death in Pca cells. NSC produced a timeand dose-dependent induction of GRP78, CHOP and XBP1s mRNA, and CHOP protein expression in Pca cells including DU145, indicating an activation of ER-stress. However, unlike conventional ER-stress in which GRP78 protein is increased, NSC produced a time-and dose-dependent U-shape change in GRP78 protein in DU145 cells. The NSC-induced decrease in GRP78 protein was blocked by protease inhibitors, N-acetyl-L-leucyl-L-leucylnorleucinal (ALLN), a lysosomal protease inhibitor, and epoxomicin (EPO), a ubiquitin-protease inhibitor. ALLN, but not EPO, also partially inhibited NSC-induced cell death. However, both 4-PBA and TUDCA, two chemical chaperons that effectively reduced tunicamycin-induced ER-stress, failed to attenuate NSC-induced GRP78, CHOP and XBP1s mRNA expression and cell death. Moreover, knockdown of NSC induction of CHOP expression using a specific siRNA had no effect on NSC-induced cytochrome c release and NSC-induced cell death. These results suggest that NSC produced an atypical ER-stress that is dissociated from NSC-induced activation of the mitochondrial apoptotic pathway and NSC-induced cell death in DU145 prostate cancer cells.

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“…Immunofluorescence staining using rabbit anti‐FABP4 (Abcam) and mouse anit‐CD31 (Abcam) antibodies was performed as previously described 35, 36. Control experiments were performed by omitting the primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

Ectopic Fatty Acid–Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury

Fuseya

Furuhashi

Matsumoto

et al. 2017

JAHA

Self Cite

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BackgroundFatty acid‐binding protein 4 (FABP4) is expressed in adipocytes, macrophages, and endothelial cells of capillaries but not arteries. FABP4 is secreted from adipocytes in association with lipolysis, and an elevated circulating FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the link between FABP4 and endovascular injury. We investigated the involvement of ectopic FABP4 expression in endothelial cells in neointima hyperplasia after vascular injury.Methods and ResultsFemoral arteries of 8‐week‐old male mice were subjected to wire‐induced vascular injury. After 4 weeks, immunofluorescence staining showed that FABP4 was ectopically expressed in endothelial cells of the hyperplastic neointima. Neointima formation determined by intima area and intima to media ratio was significantly decreased in FABP4‐defficient mice compared with that in wild‐type mice. Adenovirus‐mediated overexpression of FABP4 in human coronary artery endothelial cells (HCAECs) in vitro increased inflammatory cytokines and decreased phosphorylation of nitric oxide synthase 3. Furthermore, FABP4 was secreted from HCAECs. Treatment of human coronary smooth muscle cells or HCAECs with the conditioned medium of Fabp4‐overexpressed HCAECs or recombinant FABP4 significantly increased gene expression of inflammatory cytokines and proliferation‐ and adhesion‐related molecules in cells, promoted cell proliferation and migration of human coronary smooth muscle cells, and decreased phosphorylation of nitric oxide synthase 3 in HCAECs, which were attenuated in the presence of an anti‐FABP4 antibody.ConclusionsEctopic expression and secretion of FABP4 in vascular endothelial cells contribute to neointima formation after vascular injury. Suppression of ectopic FABP4 in the vascular endothelium would be a novel strategy against post‐angioplasty vascular restenosis.

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Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

Cited by 81 publications

References 38 publications

High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size

High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size

Dissociation of NSC606985 induces atypical ER-stress and cell death in prostate cancer cells

Ectopic Fatty Acid–Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury

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