Evidence map›Paper›PMID 40631685›Full record

ArticleCirculation research2025

GPLD1 Attenuates Heart Failure via Dual-Membrane Localization to Inhibit uPAR.

Wenjing Yu, Zhen Guo, Huimin Liang, Dinghu Ma, Chenjia Lin, Zeyu Li, Jiaying Yu, Anahita Ataran, Ali Javaheri, Zhiping Liu and 3 more

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Article in Circulation research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
  4. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Wenjing Yu *National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.ORCID 0009-0004-5356-4034
Zhen Guo *National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.ORCID 0000-0002-8421-4852
Huimin Liang *National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.
Dinghu MaNational and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.
Chenjia LinNational and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.ORCID 0009-0001-3308-3557
Zeyu LiNational and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.
Jiaying YuNational and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.
Anahita AtaranCardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (W.Y., Z.G., A.A., A.J.).ORCID 0000-0003-4426-4959
Ali JavaheriCardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (W.Y., Z.G., A.A., A.J.).ORCID 0000-0001-6657-331X
Zhiping LiuState Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou, China (Z. Liu).ORCID 0000-0001-7272-6917
Duanping SunGuangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China (D.S.).ORCID 0000-0003-1760-2975
Peiqing LiuNational and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.ORCID 0000-0002-3378-4863
Jing LuNational and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences (W.Y., Z.G., H.L., D.M., C.L., Z. Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China.ORCID 0000-0001-5766-2775

Funding

American Heart Association-American Stroke Association 24SCEFIA1253647American Heart Association-American Stroke Association 898679
6 · The paper itself

Abstract

backgroundDespite the established role of GPLD1 (glycosylphosphatidylinositol-specific phospholipase D1) in age-related impairments, its involvement in cardiovascular diseases remains unclear.

methodsWe analyzed GPLD1 transcript and protein levels in heart tissues from patients with heart failure (HF) and murine HF models. Genetic approaches, including cardiac-specific depletion, overexpression, or mutation of GPLD1, alongside intramyocardial injection of adeno-associated virus 9-mediated GPLD1 overexpression or its short hairpin RNA transduction, were used to assess the functional role of GPLD1 in transverse aortic constriction-induced HF mouse models. Proteomic profiling identified candidate binding targets, which were validated using methods including proximity ligation assay and coimmunoprecipitation. uPAR (urokinase-type plasminogen activator receptor) overexpression or short hairpin RNA targeting uPAR was performed to interrogate mechanistic pathways. Subcellular localization of GPLD1 was investigated through membrane lipid analysis and subcellular fractionation of plasma membrane and mitochondrial compartments. Cardiomyocytes were transfected with pRS426GFP-2×PH (PLC [phospholipase C] δ) to monitor phosphatidylinositol 4,5-bisphosphate levels. Cytosolic and mitochondrial calcium levels, mitochondrial permeability transition pore opening, and oxygen consumption rate were measured to evaluate cellular homeostasis and bioenergetics.

resultsGPLD1 levels were elevated in patients with HF and murine models. Cardiac-specific GPLD1 depletion exacerbated cardiac dysfunction and hypertrophy, while its overexpression ameliorated these effects, depending on enzymatic activity. uPAR was identified as a potential binding target for GPLD1, and viral-mediated uPAR transduction completely abolished the protective effects of GPLD1 following transverse aortic constriction surgery. Mechanistically, GPLD1 was anchored to the plasma membrane and outer mitochondrial membrane via phosphatidylinositol 4,5-bisphosphate to cleave the glycosylphosphatidylinositol anchor of uPAR, thereby maintaining calcium homeostasis and mitochondrial function, and ultimately ameliorating cardiac dysfunction. Conversely, excess uPAR led to a decrease in phosphatidylinositol 4,5-bisphosphate levels, preventing GPLD1 from localizing to these membranes and causing it to disperse in the cytoplasm.

conclusionsOur studies identify GPLD1 as an endogenous protective factor against HF and suggest that it may be a promising therapeutic target for cardiac dysfunction and HF.

Indexed as

Cell MembraneHeart FailureMyocytes, CardiacPhospholipase DReceptors, Urokinase Plasminogen ActivatorAnimalsDisease Models, AnimalHumansMaleMiceMice, Inbred C57BLPhospholipase DPLAUR protein, humanReceptors, Urokinase Plasminogen Activatorcell membraneheart failuremyocytes, cardiacplasminogenventricular remodeling

Identifiers

PMID40631685
PMCPMC12356483

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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.