SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

Xie, Ping; Duan, Yu; Guo, Xu; Hu, Lina; Yu, Minghua

doi:10.1159/000369671

Cited by 24 publications

(15 citation statements)

References 33 publications

(45 reference statements)

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“…Consistent with the findings of previous reports [39] , we demonstrate that the expression of apoptotic biomarkers was substantially increased in lungs of MCT-treated animals. The anti-apoptotic effects of SAA might contribute to inhibition of the development of pulmonary arterial hypertension.…”

Section: Discussionsupporting

confidence: 93%

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Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Chen¹,

Yuan²,

Zhang³

et al. 2016

Acta Pharmacol Sin

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Aim:The current therapeutic approaches have a limited effect on the dysregulated pulmonary vascular remodeling, which is characteristic of pulmonary arterial hypertension (PAH). In this study we examined whether salvianolic acid A (SAA) extracted from the traditional Chinese medicine 'Dan Shen' attenuated vascular remodeling in a PAH rat model, and elucidated the underlying mechanisms. Methods: PAH was induced in rats by injecting a single dose of monocrotaline (MCT 60 mg/kg, sc). The rats were orally treated with either SAA (0.3, 1, 3 mg·kg -1 ·d -1 ) or a positive control bosentan (30 mg·kg -1 ·d -1 ) for 4 weeks. Echocardiography and hemodynamic measurements were performed on d 28. Then the hearts and lungs were harvested, the organ indices and pulmonary artery wall thickness were calculated, and biochemical and histochemical analysis were conducted. The levels of apoptotic and signaling proteins in the lungs were measured using immunoblotting. Results: Treatment with SAA or bosentan effectively ameliorated MCT-induced pulmonary artery remodeling, pulmonary hemodynamic abnormalities and the subsequent increases of right ventricular systolic pressure (RVSP). Furthermore, the treatments significantly attenuated MCT-induced hypertrophic damage of myocardium, parenchymal injury and collagen deposition in the lungs. Moreover, the treatments attenuated MCT-induced apoptosis and fibrosis in the lungs. The treatments partially restored MCT-induced reductions of bone morphogenetic protein type II receptor (BMPRII) and phosphorylated Smad1/5 in the lungs. Conclusion: SAA ameliorates the pulmonary arterial remodeling in MCT-induced PAH rats most likely via activating the BMPRII-Smad pathway and inhibiting apoptosis. Thus, SAA may have therapeutic potential for the patients at high risk of PAH.

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Section: Discussionsupporting

confidence: 93%

“…Apoptosis from lung parenchymal damage has been well recognized in the setting of MCT-induced PAH in recent studies [38,39] . Consistent with the findings of previous reports [39] , we demonstrate that the expression of apoptotic biomarkers was substantially increased in lungs of MCT-treated animals.…”

Section: Discussionmentioning

confidence: 99%

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Chen¹,

Yuan²,

Zhang³

et al. 2016

Acta Pharmacol Sin

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“…However, the ER proteostasis may be fluctuated by a wide range of stresses, such as glucose deprivation, hypoxia, redox changes and acidosis [5][6][7]. Stresses causing accumulation of unfolded or misfolded proteins drive cell into a condition referred to as ER stress.…”

Section: Endoplasmic Reticulum (Er) Stress and The Unfolded Protein Rmentioning

confidence: 99%

IRE1α Signaling Pathways Involved in Mammalian Cell Fate Determination

Zhang

et al. 2016

Cell Physiol Biochem

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A diverse array of cellular stresses can lead to accumulation of misfolded or unfolded proteins in endoplasmic reticulum (ER), which subsequently elicits ER stress. Inositol-requiring enzyme 1α (IRE1α) is the most sensitive of the three unfolded protein response (UPR) branches which are triggered to cope with ER stress in mammalian cells. IRE1α signaling is quite context-specific on account of many adaptor and modulator proteins that directly interact with it, including heat shock proteins (HSPs), RING finger protein 13 (RNF13), poly (ADP-ribose) polymerase 16 (PARP16), Bax/Bak, and Bax inhibitor-1 (BI-1). The activated IRE1α triggers different downstream pathways depending on the UPRosome formed by distinct modulator proteins. At the initial phase of ER stress, IRE1α-XBP1 axis functions as an adaptive response. While ER stress sustains or intensifies, signals shift to apoptotic responses. Furthermore, IRE1α signaling can be exploited to the development of a wide range of prevalent human diseases, with cancer the most characterized. Here we provide an overview of recent insights into the complex IRE1α signaling network which makes IRE1α an intriguing cell fate switch. Besides, the functional relevance is presented since IRE1α activation also participates in some other physiological processes beyond protein-folding status.

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“…We investigated the effect of SFN on ER stess in cardiomyocytes undergoing H/R injury. The ER is an important membranous organelles in all eukaryotic cells, which is extremely sensitive to the stimiulation of ischemia and hypoxia [28] . Studies have shown that ER stress is a pivotal pathophysiological mechanism of myocardial ischemia reperfusion (I/R) injury [29][30][31] .…”

Section: Wwwchinapharcom LI Yp Et Almentioning

confidence: 99%

Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress

et al. 2016

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Aim: Sulforaphane (SFN), a natural dietary isothiocyanate, is found to exert beneficial effects for cardiovascular diseases. This study aimed to investigate the mechanisms underlying the protective effects of SFN in a model of myocardial hypoxia/reoxygenation (H/R) injury in vitro. Methods: Cultured neonatal rat cardiomyocytes pretreated with SFN were subjected to 3-h hypoxia followed by 3-h reoxygenation. Cell viability and apoptosis were detected. Caspase-3 activity and mitochondrial membrane potential (ΔΨm) was measured. The expression of ER stress-related apoptotic proteins were analyzed with Western blot analyses. Silent information regulator 1 (SIRT1) activity was determined with SIRT1 deacetylase fluorometric assay kit. Results: SFN (0.1-5 μmol/L) dose-dependently improved the viability of cardiomyocytes, diminished apoptotic cells and suppressed caspase-3 activity. Meanwhile, SFN significantly alleviated the damage of ΔΨm and decreased the expression of ER stress-related apoptosis proteins (GRP78, CHOP and caspase-12), elevating the expression of SIRT1 and Bcl-2/Bax ratio in the cardiomyocytes. Co-treatment of the cardiomyocytes with the SIRT1-specific inhibitor Ex-527 (1 μmol/L) blocked the SFN-induced cardioprotective effects. Conclusion: SFN prevents cardiomyocytes from H/R injury in vitro most likely via activating SIRT1 pathway and subsequently inhibiting the ER stress-dependent apoptosis.

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SalA Attenuates Hypoxia-Induced Endothelial Endoplasmic Reticulum Stress and Apoptosis via Down-Regulation of VLDL Receptor Expression

Cited by 24 publications

References 33 publications

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

Salvianolic acid A attenuates vascular remodeling in a pulmonary arterial hypertension rat model

IRE1α Signaling Pathways Involved in Mammalian Cell Fate Determination

Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress

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