The role of endothelial cells in pulmonary hypertension: old concepts and new science

Haensel, Maike; Wójciak-Stothard, Beata

doi:10.1016/j.cophys.2023.100667

Cited by 4 publications

(1 citation statement)

References 73 publications

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“…These conditions perturb mechanotransduction and cytoskeletal organization preventing the development of the EC phenotypes found in the human body. Recently, the use of lung-on-a-chip technologies has overcome many of the limitations of human EC cultures ( 14 , 15 ). However, even when using these technologies, the results are general and the physiological conditions of a PH patient may differ from those used in a study.…”

Section: Introductionmentioning

confidence: 99%

A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

Weinstein,

Carlsen,

Schulz

et al. 2024

Front. Cardiovasc. Med.

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IntroductionPulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation.MethodsUsing our graph-powered knowledge mining software Lifelike in combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs.ResultsIn PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities of Lifelike, led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH. Lifelike elucidated the interplay between G-protein, IL6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis.DiscussionThe results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs using Lifelike’s diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe that Lifelike and our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.

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Section: Introductionmentioning

confidence: 99%

A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

Weinstein,

Carlsen,

Schulz

et al. 2024

Front. Cardiovasc. Med.

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Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling

Pokharel,

Fu,

Garcia-Flores

et al. 2024

Free Radical Biology and Medicine

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ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

Weinstein,

Carlsen,

Schulz

et al. 2023

Preprint

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Pulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation. Using our graph-powered knowledge mining softwareLifelikein combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs. In PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities ofLifelike, led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to Activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH.Lifelikeelucidated the interplay between G-protein, interleukin 6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis. The results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs usingLifelike’s diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe thatLifelikeand our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.

show abstract

The role of endothelial cells in pulmonary hypertension: old concepts and new science

Cited by 4 publications

References 73 publications

A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

A Lifelike guided journey through the pathophysiology of pulmonary hypertension—from measured metabolites to the mechanism of action of drugs

Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling

ALifelikeguided journey through the pathophysiology of pulmonary hypertension - from measured metabolites to the mechanism of action of drugs

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