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

Wenjing Yu^1,2, Zhen Guo^1,2, Huimin Liang¹

¹National 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.

Circulation Research

|July 9, 2025

Summary

This summary is machine-generated.

Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) protects against heart failure (HF) by maintaining cellular homeostasis and mitochondrial function. Urokinase-type plasminogen activator receptor (uPAR) interaction is key to GPLD1’s protective effects in cardiac dysfunction.

Keywords:

cell membrane heart failure myocytes, cardiac plasminogen ventricular remodeling

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Published on: April 24, 2021

Area of Science:

Cardiovascular Biology
Molecular Medicine
Biochemistry

Background:

The role of glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) in age-related impairments is known, but its function in cardiovascular diseases, particularly heart failure (HF), is not well understood.
Investigating GPLD1's involvement in HF is crucial for identifying novel therapeutic targets.

Purpose of the Study:

To elucidate the role and mechanism of GPLD1 in the pathogenesis of heart failure.
To determine if GPLD1 can serve as a therapeutic target for cardiac dysfunction.

Main Methods:

Analysis of GPLD1 and uPAR (urokinase-type plasminogen activator receptor) levels in human HF patients and murine HF models.
Genetic manipulation of GPLD1 and uPAR in cardiac-specific mouse models of HF.
Proteomic analysis to identify GPLD1 binding partners and mechanistic studies involving cellular signaling pathways, membrane localization, and mitochondrial function.

Main Results:

GPLD1 levels were elevated in HF patients and models. Cardiac-specific GPLD1 depletion worsened HF, while overexpression improved cardiac function.
GPLD1 interacts with uPAR, and this interaction is essential for its protective effects. GPLD1 localizes to the plasma and mitochondrial membranes to cleave uPAR's anchor, preserving calcium and mitochondrial homeostasis.
uPAR overexpression disrupted GPLD1 localization and function, exacerbating cardiac dysfunction.

Conclusions:

GPLD1 acts as an endogenous protective factor against heart failure.
Targeting GPLD1 represents a potential therapeutic strategy for treating cardiac dysfunction and HF.