New Drugs and Therapies in Pulmonary Arterial Hypertension

Shah, Aangi; Beckmann, Taylor; Vorla, Mounica

doi:10.3390/ijms24065850

Cited by 14 publications

(10 citation statements)

References 250 publications

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“…PH is a complex disease process involving multiple molecular mechanisms and chronic environmental, metabolic, genetic, and hypoxic insults resulting in pathologic remodeling of primarily medium- and small-sized pulmonary arterioles ( 202 ). The progression of pulmonary vascular remodeling in PH is driven by dynamic and local dysfunctions of both the pulmonary endothelium and vascular smooth muscle.…”

Section: Discussionmentioning

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: Discussionmentioning

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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show abstract

“…Hypotheses concerning the mechanism of action of existing and novel pharmacological treatments of PH (Table 3) and their clinical implications PH is a complex disease process involving multiple molecular mechanisms and chronic environmental, metabolic, genetic, and hypoxic insults resulting in pathologic remodeling of primarily medium-and small-sized pulmonary arterioles [202]. The progression of pulmonary vascular remodeling in PH is driven by dynamic and local dysfunctions of both the pulmonary endothelium and vascular smooth muscle.…”

Section: 4mentioning

confidence: 99%

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.

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“…Previous clinical treatment strategies for PH have primarily focused on the excessive vasoconstriction of pulmonary blood vessels. However, the structural damage to blood vessels limits the efficacy of vasodilator drugs ( Shah et al, 2023 ). Nevertheless, the successful application of NO, the first gaseous signaling molecule used in the treatment of PH, provides a positive reference for the treatment of clinical PH with SO 2 ( Yu et al, 2019 ).…”

Section: Significance and Prospects Of So 2 In Phmentioning

confidence: 99%

Advances in the research of sulfur dioxide and pulmonary hypertension

Liu,

Zhou,

Zhang

et al. 2023

Front. Pharmacol.

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Pulmonary hypertension (PH) is a fatal disease caused by progressive pulmonary vascular remodeling (PVR). Currently, the mechanisms underlying the occurrence and progression of PVR remain unclear, and effective therapeutic approaches to reverse PVR and PH are lacking. Since the beginning of the 21st century, the endogenous sulfur dioxide (SO2)/aspartate transaminase system has emerged as a novel research focus in the fields of PH and PVR. As a gaseous signaling molecule, SO2 metabolism is tightly regulated in the pulmonary vasculature and is associated with the development of PH as it is involved in the regulation of pathological and physiological activities, such as pulmonary vascular cellular inflammation, proliferation and collagen metabolism, to exert a protective effect against PH. In this review, we present an overview of the studies conducted to date that have provided a theoretical basis for the development of SO2-related drug to inhibit or reverse PVR and effectively treat PH-related diseases.

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New Drugs and Therapies in Pulmonary Arterial Hypertension

Cited by 14 publications

References 250 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

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

Advances in the research of sulfur dioxide and pulmonary hypertension

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