Heat stress prevents lipopolysaccharide-induced apoptosis in pulmonary microvascular endothelial cells by blocking calpain/p38 MAPK signalling

Liu, Zhifeng; Zheng, Dong; Fan, Guo-Chang; Peng, Tianqing; Su, Lei

doi:10.1007/s10495-016-1263-0

Cited by 39 publications

(26 citation statements)

References 47 publications

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“…The results of this study suggest that the proapoptotic role of calpain is related to caspase-3 activation, since Capn4 knockout abolished caspase-3 activation and DNA fragmentation in kidney tissue. In addition, we found that this proapoptotic effect was related to the phosphorylation of p38, similar to the findings in our previous study 17 . MAPKs are a family of serine/threonine kinases, and the ERK, JNK and p38 pathways are the three classical MAPK pathways in mammals and mediate various cellular processes, including cell proliferation, apoptosis, and stress responses 28 .…”

Section: Discussionsupporting

confidence: 92%

“…Calpain activation exerts a proapoptotic effect in mice with sepsis and in LPS-treated cultured cells, including cardiomyocytes and endothelial, diaphragm and skeletal muscle cells 16,17,24,25 . Since calpain is a protease, its proapoptotic effect is attributable mainly to its degradative properties.…”

Section: Discussionmentioning

confidence: 99%

“…PMECs were isolated from adult C57BL/6 mice and cultured as previously described 17 . All PMECs were used for this study within 5 passages.…”

Section: Pmec Culture and Treatmentsmentioning

confidence: 99%

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Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Liu

Zheng

et al. 2020

Exp Mol Med

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To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4 −/− ), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4 −/− ). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogenactivated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4 −/− and Tg-CAST mice but not in LYZ/ Capn4 −/− mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Liu

Zheng

et al. 2020

Exp Mol Med

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“…Given that p38 mitogen-activated protein kinase also causes a release of pro-inflammatory EMPs (Curtis et al 2009), it stands to reason that reduced p38 activity with heat stress might contribute to the reduction in both PMPs and EMPs reported in the present study. In fact, heat stress (Liu et al 2016b) and heat stress pretreatment (Liu et al 2016a) inhibit lipolysaccharide-induced apoptosis via inhibition of the p38 signalling pathway. Decreased EMPs in passive heat stress might also result from changes in blood flow shear patterns; that is, passive heat stress increases anterograde and decreases retrograde shear rate (Romero et al 2017).…”

Section: Baselinementioning

confidence: 99%

Passive heat stress reduces circulating endothelial and platelet microparticles

Bain

Ainslie

Bammert

et al. 2017

Experimental Physiology

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What is the central question of this study? Does passive heat stress of +2°C oesophageal temperature change concentrations of circulating arterial endothelial- and platelet-derived microparticles in healthy adults? What is the main finding and its importance? Concentrations of circulating endothelial- and platelet-derived microparticles were markedly decreased in heat stress. Reductions in circulating microparticles might indicate favourable vascular changes associated with non-pathological hyperthermia. Interest in circulating endothelial- and platelet-derived microparticles (EMPs and PMPs, respectively) has increased because of their potential pathogenic role in vascular disease and as biomarkers for vascular health. Hyperthermia is commonly associated with a pro-inflammatory stress but might also provide vascular protection when the temperature elevation is non-pathological. Circulating microparticles might contribute to the cellular adjustments and resultant vascular impacts of hyperthermia. Here, we determined whether circulating concentrations of arterial EMPs and PMPs are altered by passive heat stress (+2°C oesophageal temperature). Ten healthy young men (age 23 ± 3 years) completed the study. Hyperthermia was achieved by circulating ∼49°C water through a water-perfused suit that covered the entire body except the hands, feet and head. Arterial (radial) blood samples were obtained immediately before heating (normothermia) and in hyperthermia. The mean ± SD oesophageal temperature in normothermia was 37.2 ± 0.1°C and in hyperthermia 39.1 ± 0.1°C. Concentrations of circulating EMPs and PMPs were markedly decreased in hyperthermia. Activation-derived EMPs were reduced by ∼30% (mean ± SD; from 61 ± 8 to 43 ± 7 microparticles μl ; P < 0.05) and apoptosis-derived EMPs by ∼45% (from 46 ± 7 to 23 ± 3 microparticles μl ; P < 0.05). Likewise, circulating PMPs were reduced by ∼75% in response to hyperthermia (from 256 ± 43 to 62 ± 14 microparticles μl ). These beneficial reductions in circulating EMPs and PMPs in response to a 2°C increase in core temperature might partly underlie the reported vascular improvements following therapeutic bouts of physiological hyperthermia.

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“…A recent study has demonstrated that inhibition of calpain preserves memory and reduces accumulation of Aβ and of p25 in mouse model of AD [14]. Moreover, the function of calpain in cardiovascular diseases have been extensively investigated [15][16][17][18][19]. Although there is accumulating evidence that targeted inhibition of calpain serves as a potential therapeutic strategy for calpain related diseases in animal models and clinical trials, few studied have investigated the roles of calpains in autoimmune diseases [5,20].…”

Section: Introductionmentioning

confidence: 99%

Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis

Zheng

Yan

et al. 2020

Preprint

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Background Systemic sclerosis (SSc) or scleroderma is an intractable autoimmune disorder that affects multiple organs. The objectives were to investigate clinical correlations of serum calpain activity and high mobility group box 1 (HMGB1) levels with immunological and clinical traits. Methods A total of 31 patients with SSc, 20 age- and gender-matched healthy control subjects (HC) and 10 patients with other connective tissue diseases (CTD) were recruited in the study. We measured serum calpain activity and HMGB1 levels and analyzed the datasets (GSE40839, GSE48149, GSE76808, GSE81292 and GSE33463) from gene expression omnibus (GEO) database to explore potential mechanism by which calpain exerts its function through bioinformatics methods. Results Serum calpain activity was significantly increased in patients with SSc compared with those in HC and in patients with CTD and was correlated with serum HMGB1 levels, modified Rodnan skin score, erythrocyte sedimentation rate, mean platelet volume and plateletcrit. Notably, serum calpain activity and HMGB1 levels in SSc patients with interstitial lung disease (ILD) were significantly higher than that in SSc patients without ILD. Serum calpain activity and HMGB1 levels could be the independent risk factors for SSc-ILD and novel biomarkers in patients with SSc. Conclusion This is the first study that reports increased serum calpain activity and the correlation between calpain and HMGB1 in patients with SSc or SSc-ILD. The serum calpain activity and HMGB1 levels may serve as measures of ILD in patients with SSc. Also, calpain and HMGB1 could be potentially therapeutic targets for patients with SSc or SSc-ILD in the future.

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Heat stress prevents lipopolysaccharide-induced apoptosis in pulmonary microvascular endothelial cells by blocking calpain/p38 MAPK signalling

Cited by 39 publications

References 47 publications

Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Passive heat stress reduces circulating endothelial and platelet microparticles

Increased serum calpain activity is associated with HMGB1 levels in systemic sclerosis

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