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

作者：Wenjing Yu, Zhen Guo, Huimin Liang, Dinghu Ma, Chenjia Lin, Zeyu Li, Jiaying Yu, Anahita Ataran, Ali Javaheri, Zhiping Liu, Duanping Sun, Peiqing Liu, Jing Lü · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.124.325623 · 被引用次数：7 · 研究领域：Caveolin-1 and cellular processes、Systemic Lupus Erythematosus Research、Cell Adhesion Molecules Research

BACKGROUND: Despite the established role of GPLD1 (glycosylphosphatidylinositol-specific phospholipase D1) in age-related impairments, its involvement in cardiovascular diseases remains unclear. METHODS: 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-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. RESULTS: GPLD1 levels were elevated...