A critical appraisal of the role of intracellular Ca2+-signaling pathways in Kawasaki disease

Bijnens, Jeroen; Missiaen, Ludwig; Bultynck, Geert; Parys, Jan B.

doi:10.1016/j.ceca.2018.01.002

Cited by 8 publications

(5 citation statements)

References 116 publications

(183 reference statements)

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“…Indeed, many investigators have reported that Piezo1, an important cation channel to enable shear-or stretch-mediated Ca 2 þ influx in endothelial cells, is involved in nitric oxide (NO) synthase (eNOS)-and EDRF/EDNOmediated vasodilation (4,15,74,78). However, sustained or prolonged increase of the resting [Ca 2 þ ] cyt in ECs to an abnormal level has been implicated in vascular diseases (79,80). It is possible that, under normal and physiological conditions, Ca 2 þ influx through Piezo1 channels in PAECs, is involved in mediating EDNO-mediated pulmonary vasodilation.…”

Section: Discussionmentioning

confidence: 99%

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Wang

Chen

Babicheva

et al. 2021

American Journal of Physiology-Cell Physiology

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Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared to normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, while downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

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Section: Discussionmentioning

confidence: 99%

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Wang

Chen

Babicheva

et al. 2021

American Journal of Physiology-Cell Physiology

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“…Molecular pathophysiology is still unclear, however a number of implicated genes have been suggested in the passing years. Recent reviews point to enhanced T Cell activation (ITPKC, ORAI1, STIM1), dysregulated B Cell signaling (CD40, BLK, FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta (TGFB) signaling as major molecular mechanisms of KD ( Bijnens et al, 2018 ; Kumrah et al, 2020 ). The map constructed with our workflow captures and highlights some of the pathways involved in KD.…”

Section: Resultsmentioning

confidence: 99%

Visualization of automatically combined disease maps and pathway diagrams for rare diseases

et al. 2023

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Introduction: Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower.Methods: In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer.Results: We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets.Discussion: In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.

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“…More in general, ITPR3-mediated pathways have been also linked to ischemic heart disease [86] and coronary artery disease [102]. ITPR3 has been associated with the risk of developing coronary artery aneurism in Taiwanese children with Kawasaki disease [103], a multisystemic vasculitis that can result in coronary artery lesions and that had been linked to aberrant calcium signaling [104]. In a case-control study involving 93 Kawasaki disease patients and 680 healthy controls, the frequency of the rs2229634 T/T genotype was significantly higher in Kawasaki disease patients with coronary artery aneurism than in patients without coronary artery aneurism [103].…”

Section: Potential Role Of Itprs In Human Disease: Evidence From Gwasmentioning

confidence: 99%

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

Gambardella

Lombardi

Morelli

et al. 2020

JCM

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Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

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A critical appraisal of the role of intracellular Ca2+-signaling pathways in Kawasaki disease

Cited by 8 publications

References 116 publications

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Visualization of automatically combined disease maps and pathway diagrams for rare diseases

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

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