Gatto Cristina, Rusciano Maria Rosaria, Sorriento Daniela, Di Pietro Paola, Abate Angela Carmelita, Visco Valeria, Montone Nicola, Mone Pasquale, Di Napoli Daniele, Chivasso Pierpaolo, Bruno Vito Domenico, Valerio Vincenza, Poggio Paolo, Iaccarino Guido, Santulli Gaetano, Vecchione Carmine, Carrizzo Albino, Ciccarelli Michele
University of Salerno "Scuola Medica Salernitana", Department of Medicine, Surgery and Dentistry, 84081, Baronissi, Italy.
University of Salerno "Scuola Medica Salernitana", Scuola di Specializzazione in Patologia Clinica e Biochimica Clinica, 84081, Baronissi, Italy.
Cell Death Discov. 2025 Jul 14;11(1):324. doi: 10.1038/s41420-025-02628-0.
Hypoxia, a condition characterized by a temporary lack of oxygen, causes mitochondrial damage, which in turn leads to endothelial dysfunction. G-protein-coupled receptor kinase 2 (GRK2) plays a key role in vascular homeostasis and remodeling, influencing endothelial function through various pathways. GRK2 moves within the cellular compartments and is linked to mitochondrial function and biogenesis, promoting ATP production and protecting against oxidative stress and cell death. The present study examined how mitochondrial GRK2 accumulation affects vascular reactivity and endothelial function in transient hypoxic conditions. Using a cloning strategy, we employed a small peptide (10aa) TAT-conjugated based on the pleckstrin homology domain of GRK2 to redirect GRK2 from the plasma membrane to the mitochondria. Mitochondrial accumulation of GRK2 increases vasodilatory responses in isolated swine artery segments, indicating potential therapeutic applications for cardiovascular disorders. Furthermore, in endothelial cells, GRK2 accumulation within mitochondria protects membrane potential, mitochondrial mass and prevents oxidative damage and cell death caused by transient hypoxia. Our findings show that GRK2 accumulation in mitochondria represents a potential therapeutic target to prevent transient hypoxia-induced damage.
缺氧是一种以暂时缺氧为特征的状况，会导致线粒体损伤，进而引发内皮功能障碍。G蛋白偶联受体激酶2（GRK2）在血管稳态和重塑中起关键作用，通过多种途径影响内皮功能。GRK2在细胞区室间移动，并与线粒体功能和生物发生相关联，促进ATP生成，抵御氧化应激和细胞死亡。本研究探讨了线粒体GRK2积累如何影响短暂缺氧条件下的血管反应性和内皮功能。我们采用克隆策略，基于GRK2的普列克底物蛋白同源结构域，使用一种小肽（10个氨基酸）与TAT偶联，将GRK2从质膜重定向至线粒体。GRK2在线粒体中的积累增加了离体猪动脉段的血管舒张反应，表明其在心血管疾病方面具有潜在的治疗应用。此外，在内皮细胞中，GRK2在线粒体内的积累可保护膜电位、线粒体质量，并防止短暂缺氧引起的氧化损伤和细胞死亡。我们的研究结果表明，GRK2在线粒体中的积累是预防短暂缺氧诱导损伤的一个潜在治疗靶点。
