Mitochondrial accumulation of GRK2 as a protective mechanism against hypoxia-induced endothelial dysfunction
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.
Authors
- Paola Di Pietro (ORCID: https://orcid.org/0000-0003-1327-1961)
- Michele Ciccarelli (ORCID: https://orcid.org/0000-0003-2379-1960)
- Cristina Gatto (ORCID: https://orcid.org/0000-0003-1658-8470)
- Guido Iaccarino (ORCID: https://orcid.org/0000-0002-8997-835X)
- Gaetano Santulli (ORCID: https://orcid.org/0000-0001-7231-375X)
- Valeria Visco (ORCID: https://orcid.org/0000-0002-2197-5355)
- Vito Domenico Bruno (ORCID: https://orcid.org/0000-0002-8193-9559)
- Daniela Sorriento (ORCID: https://orcid.org/0000-0002-1599-4509)
- Pierpaolo Chivasso (ORCID: https://orcid.org/0000-0001-5575-2275)
- Maria Rosaria Rusciano (ORCID: https://orcid.org/0000-0002-7112-6503)
- Albino Carrizzo (ORCID: https://orcid.org/0000-0003-2689-0008)
- Pasquale Mone (ORCID: https://orcid.org/0000-0001-6267-5845)
- Angela Carmelita Abate (ORCID: https://orcid.org/0009-0007-2811-8018)
- Vincenza Valerio (ORCID: https://orcid.org/0000-0002-6344-267X)
- Carmine Vecchione (ORCID: https://orcid.org/0000-0002-2473-4565)
- Paolo Poggio (ORCID: https://orcid.org/0000-0002-7225-3379)
- Daniele Di Napoli
- Nicola Montone
Institutions
- University of Molise (IT)
- Albert Einstein College of Medicine (US)
- University of Salerno (IT)
- Feinstein Institute for Medical Research (US)
- University of Milan (IT)
- Istituto Neurologico Mediterraneo (IT)
- Hodges University (US)
- Centro Cardiologico Monzino (IT)
- Istituto Clinico Sant'Ambrogio (IT)
- Federico II University Hospital (IT)
- Casa di cura Pierangeli (IT)
- Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT)
Publication Details
- Journal
- Cell Death Discovery
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1038/s41420-025-02628-0
- Citations
- 1
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.81