Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death

Becerra, Alvaro; Echeverría, César; Varela, Diego; Sarmiento, Daniela; Armisén, Ricardo; Nuñez-Villena, Felipe; Montecinos, M. I.; Simón, Felipe

doi:10.1093/cvr/cvr135

Cited by 80 publications

(74 citation statements)

References 42 publications

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“…7,[67][68][69][70][71][72] Thus, ameliorating oxidative stressinduced conversion of ECs into myofibroblasts with antioxidants and reducing agents could be useful for treatment.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

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119

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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“…7,[67][68][69][70][71][72] Thus, ameliorating oxidative stressinduced conversion of ECs into myofibroblasts with antioxidants and reducing agents could be useful for treatment.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

Self Cite

119

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“…It has previously been demonstrated that TRPM4 mRNA is widely expressed in numerous types of tissue, the highest mRNA transcript levels being found in the prostate and the intestines [13]. Whereas the physiological function of TRPM4 in the prostate is unknown, it is involved in such diverse functions as depolarisation of vascular smooth muscle cells [25], regulation of sinus rhythm of the heart [26] and the process of cell death through Na + influx [27]. Furthermore, TRPM4 expression is upregulated in an aggressive form of large B-cell non-Hodgkin lymphoma [28], and high expression has been found to correlate with tumour progression and metastatic disease [18,28].…”

Section: Discussionmentioning

confidence: 99%

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

et al. 2015

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BACKGROUND Transient receptor potential cation channel, subfamily M, member 4 (TRPM4) messenger RNA (mRNA) has been shown to be upregulated in prostate cancer (PCa) and might be a new promising tissue biomarker. We evaluated TRPM4 protein expression and correlated the expression level with biochemical recurrence (BR) following radical prostatectomy (RP). MATERIAL AND METHODS The study included 614 patients who had undergone RP. TRPM4 immunohistochemical staining was performed on samples of benign tissue, tissue containing PIN glands and PCa tissue using a commercially available polyclonal antibody. Staining intensity was recorded by two independent observers using a four-tired semi-quantitative grading system (0, 1+, 2+, 3+) converted into H-scores. Interobserver agreement was calculated by linear weighted kappa statistics. The association between staining intensity and BR was analysed using the Kaplan-Meier estimator and uni-and multiple Cox proportional hazard regression models. RESULTS Significantly higher staining intensity was found in PCa glands compared to benign glands (p < 0.001). The concordance rate in TRPM4 staining intensities for benign, PIN and PCa tissue ranged from 86.0 to 91.5 %, corresponding to linear weighted kappa values of 0.566-0.789. After adjusting for patient and tumour characteristics, patients with a higher staining intensity in PCa glands compared to matched benign glands and an H-score equal to or above the median had an increased risk of BR (HR 1.79-2.62; p = 0.01-0.03 for the two observers) when compared to patients with a lower staining intensity. CONCLUSIONS TRPM4 protein expression is widely expressed in benign and cancerous prostate tissue, with highest staining intensities found in PCa. Overexpression of TRPM4 in PCa (combination of high staining intensity and a high H-score) is associated with increased risk of BR after RP.

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“…4) activation of TRPM4 channel by ATP depletion in COS-7 Channels and Cell Volume cells leads to depolarization and progressive bleb formation (Chen and Simard, 2001;Chen et al, 2003), but this is not observed in cells lacking the channel (Simard et al, 2012). 5) Induced upregulation of TRPM4 protein in endothelial cells from human umbilical vein causes Na 1 overload, cell volume increase, and necrotic death, effects which are prevented by pharmacologic inhibition of the channel (Gerzanich et al, 2009;Becerra et al, 2011). It should be noted that ADP and AMP are reported to block TRPM4b currents ; however, during the first minutes of ischemia, ADP levels decrease in parallel to the increase in ATP and AMP levels (Guarnieri et al, 1993;Phillis et al,1995).…”

Section: Channels Involved In Volume Changes In Necrotic and Apoptotimentioning

confidence: 99%

Channels and Volume Changes in the Life and Death of the Cell

Pasantes‐Morales

2016

Mol Pharmacol

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Volume changes deviating from original cell volume represent a major challenge for cellular homeostasis. Cell volume may be altered either by variations in the external osmolarity or by disturbances in the transmembrane ion gradients that generate an osmotic imbalance. Cells respond to anisotonicity-induced volume changes by active regulatory mechanisms that modify the intracellular/extracellular concentrations of K 1 , Cl -, Na 1 , and organic osmolytes in the direction necessary to reestablish the osmotic equilibrium. Corrective osmolyte fluxes permeate across channels that have a relevant role in cell volume regulation. Channels also participate as causal actors in necrotic swelling and apoptotic volume decrease. This is an overview of the types of channels involved in either corrective or pathologic changes in cell volume. The review also underlines the contribution of transient receptor potential (TRP) channels, notably TRPV4, in volume regulation after swelling and describes the role of other TRPs in volume changes linked to apoptosis and necrosis. Lastly we discuss findings showing that multimers derived from LRRC8A (leucine-rich repeat containing 8A) gene are structural components of the volume-regulated Cl -channel (VRAC), and we underline the intriguing possibility that different heteromer combinations comprise channels with different intrinsic properties that allow permeation of the heterogenous group of molecules acting as organic osmolytes.

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Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death

Cited by 80 publications

References 42 publications

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy

Channels and Volume Changes in the Life and Death of the Cell

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