{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T06:07:54Z","timestamp":1792822074764,"version":"4.5.0"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,8,15]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Despite the established role of GPLD1 (glycosylphosphatidylinositol-specific phospholipase D1) in age-related impairments, its involvement in cardiovascular diseases remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We 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\u2013mediated GPLD1 overexpression or its short hairpin RNA transduction, were used to assess the functional role of GPLD1 in transverse aortic constriction\u2013induced 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\u00d7PH (PLC [phospholipase C] \u03b4) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>GPLD1 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.325623","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T11:40:41Z","timestamp":1752061241000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["GPLD1 Attenuates Heart Failure via Dual-Membrane Localization to Inhibit uPAR"],"prefix":"10.1161","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5356-4034","authenticated-orcid":true,"given":"Wenjing","family":"Yu","sequence":"first","affiliation":[{"name":"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."},{"name":"Cardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (W.Y., Z.G., A.A., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8421-4852","authenticated-orcid":true,"given":"Zhen","family":"Guo","sequence":"additional","affiliation":[{"name":"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."},{"name":"Cardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (W.Y., Z.G., A.A., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Liang","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinghu","family":"Ma","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3308-3557","authenticated-orcid":true,"given":"Chenjia","family":"Lin","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Li","sequence":"additional","affiliation":[{"name":"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."},{"name":"Department of Cardiac Surgery, First Affiliated Hospital (Z. Li), Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaying","family":"Yu","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4426-4959","authenticated-orcid":true,"given":"Anahita","family":"Ataran","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (W.Y., Z.G., A.A., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6657-331X","authenticated-orcid":true,"given":"Ali","family":"Javaheri","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO (W.Y., Z.G., A.A., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7272-6917","authenticated-orcid":true,"given":"Zhiping","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou, China (Z. 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Li, J.Y., P.L., J.L.), Sun Yat-sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5766-2775","authenticated-orcid":true,"given":"Jing","family":"Lu","sequence":"additional","affiliation":[{"name":"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. 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