Evidence map›Paper›PMID 39162036›Full record

ArticleHypertension (Dallas, Tex. : 1979)2024

Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.

Danchen Wu, Ross D Jansen-van Vuuren, Asish Dasgupta, Ruaa Al-Qazazi, Kuang-Hueih Chen, Ashley Y Martin, Jeffrey D Mewburn, Elahe Alizadeh, Patricia D A Lima, Oliver Jones and 12 more

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Article in Hypertension (Dallas, Tex. : 1979), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Danchen WuDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-3901-5907
Ross D Jansen-van VuurenFaculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia (R.D.J.-v.V., L.J.).
Asish DasguptaDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0002-3670-1197
Ruaa Al-QazaziDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-0983-9745
Kuang-Hueih ChenDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.
Ashley Y MartinDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0009-0005-8170-1638
Jeffrey D MewburnDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0002-1365-4228
Elahe AlizadehQueen's Cardiopulmonary Unit, Department of Medicine (E.A., P.D.A.L., O.J., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-4046-1226
Patricia D A LimaQueen's Cardiopulmonary Unit, Department of Medicine (E.A., P.D.A.L., O.J., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0002-6456-2470
Oliver JonesQueen's Cardiopulmonary Unit, Department of Medicine (E.A., P.D.A.L., O.J., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0009-0008-6398-2052
Pierce ColpmanDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.
Rachel E T BentleyDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-0486-8467
M Martin VandenBroekDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-4937-2502
Nolan M BreaultDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.
Isaac M EmonDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0009-0002-6375-1074
V Siddartha YerramilliDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0002-4562-682X
Luka JedlovčnikFaculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia (R.D.J.-v.V., L.J.).ORCID 0000-0002-9879-2573
Yuan Yuan ZhaoDepartment of Medicine, University of Alberta, Edmonton, Canada (Y.Y.Z., G.S.).
Michael WellsPartnerships and Innovation (M.W.), Queen's University, Kingston, Ontario, Canada.
Gopinath SutendraDepartment of Medicine, University of Alberta, Edmonton, Canada (Y.Y.Z., G.S.).ORCID 0000-0002-8181-1483
Mark L OrmistonDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-0907-1940
Stephen L ArcherDepartment of Medicine (D.W., A.D., R.A.-Q., K.-H.C., A.Y.M., J.D.M., P.C., R.E.T.B., M.M.V., N.M.B., I.M.E., V.S.Y., M.L.O., S.L.A.), Queen's University, Kingston, Ontario, Canada.ORCID 0000-0003-1106-3202

Funding

O2 sensing in the human and rabbit ductus arteriosus.R01HL071115 · NHLBI · UNIVERSITY OF CHICAGO · PI ARCHER, STEPHEN L · 2004 to 2015
$3.1M
The Role of DRP-1 and Mitochondrial Fission in Pulmonary Arterial HypertensionR01HL113003 · NHLBI · QUEEN'S UNIVERSITY AT KINGSTON · PI ARCHER, STEPHEN L · 2013 to 2016
$1.1M
Impaired mitochondrial fusion in pulmonary arterial hypertensionRC1HL099462 · NHLBI · UNIVERSITY OF CHICAGO · PI ARCHER, STEPHEN L · 2009 to 2010
$1.0M
NHLBI NIH HHS R01 HL071115NHLBI NIH HHS R01 HL113003NHLBI NIH HHS RC1 HL099462
6 · The paper itself

Abstract

backgroundDrp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown.

methodsDrpitor1a's ability to inhibit recombinant and endogenous Drp1 GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in control and monocrotaline-PAH females.

resultsDrp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity.

conclusionsDrpitor1a is a specific Drp1 GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.

Indexed as

ApoptosisCell ProliferationDynaminsHypertension, PulmonaryMitochondrial DynamicsMyocytes, Smooth MusclePulmonary ArteryAnimalsCells, CulturedDisease Models, AnimalEndothelial CellsFemaleGTP PhosphohydrolasesHumansMaleMiddle AgedDNM1L protein, humanDynaminsGTP Phosphohydrolasesendothelial cellsGTP phosphohydrolasesmitochondrial dynamicsmonocrotalinepulmonary arterial hypertension

Identifiers

PMID39162036
PMCPMC11410511

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.