Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction
Abstract 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...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02628-0 |
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| author | Cristina Gatto Maria Rosaria Rusciano Daniela Sorriento Paola Di Pietro Angela Carmelita Abate Valeria Visco Nicola Montone Pasquale Mone Daniele Di Napoli Pierpaolo Chivasso Vito Domenico Bruno Vincenza Valerio Paolo Poggio Guido Iaccarino Gaetano Santulli Carmine Vecchione Albino Carrizzo Michele Ciccarelli |
| author_facet | Cristina Gatto Maria Rosaria Rusciano Daniela Sorriento Paola Di Pietro Angela Carmelita Abate Valeria Visco Nicola Montone Pasquale Mone Daniele Di Napoli Pierpaolo Chivasso Vito Domenico Bruno Vincenza Valerio Paolo Poggio Guido Iaccarino Gaetano Santulli Carmine Vecchione Albino Carrizzo Michele Ciccarelli |
| author_sort | Cristina Gatto |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-a85f74a9ca4842a7a877f975cea00ce2 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-a85f74a9ca4842a7a877f975cea00ce22025-08-20T03:42:47ZengNature Publishing GroupCell Death Discovery2058-77162025-07-0111111110.1038/s41420-025-02628-0Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunctionCristina Gatto0Maria Rosaria Rusciano1Daniela Sorriento2Paola Di Pietro3Angela Carmelita Abate4Valeria Visco5Nicola Montone6Pasquale Mone7Daniele Di Napoli8Pierpaolo Chivasso9Vito Domenico Bruno10Vincenza Valerio11Paolo Poggio12Guido Iaccarino13Gaetano Santulli14Carmine Vecchione15Albino Carrizzo16Michele Ciccarelli17University of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryFederico II University Hospital, Department of Advanced Biomedical SciencesUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Molise, Department of Medicine and Health Sciences “Vincenzo Tiberio”University of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity Hospital “San Giovanni Di Dio e Ruggi D’Aragona, Department of Emergency Cardiac Surgery, Cardio-Thoracic-VascularIRCCS Institute Galeazzi Sant’Ambrogio, Department of Minimal Clinical Cardio SurgeryCardiology Center Monzino IRCCSCardiology Center Monzino IRCCSFederico II University Hospital, Department of Clinical Medicine and SurgeryEinstein Institute for Aging Research, Einstein Institute for Neuroimmunology and Neuroinflammation, Albert Einstein College of Medicine, Department of MedicineUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryUniversity of Salerno “Scuola Medica Salernitana”, Department of Medicine, Surgery and DentistryAbstract 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.https://doi.org/10.1038/s41420-025-02628-0 |
| spellingShingle | Cristina Gatto Maria Rosaria Rusciano Daniela Sorriento Paola Di Pietro Angela Carmelita Abate Valeria Visco Nicola Montone Pasquale Mone Daniele Di Napoli Pierpaolo Chivasso Vito Domenico Bruno Vincenza Valerio Paolo Poggio Guido Iaccarino Gaetano Santulli Carmine Vecchione Albino Carrizzo Michele Ciccarelli Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction Cell Death Discovery |
| title | Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction |
| title_full | Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction |
| title_fullStr | Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction |
| title_full_unstemmed | Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction |
| title_short | Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction |
| title_sort | mitochondrial accumulation of grk2 as a protective mechanism against hypoxia induced endothelial dysfunction |
| url | https://doi.org/10.1038/s41420-025-02628-0 |
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