title: [The Role of GRK2 and Its Potential as a New Therapeutic Target in Diabetic Vascular Complications].
abstract: A decrease in nitric oxide (NO) production may induce pathological conditions associated with endothelial dysfunction and diabetes. Although a decrease in NO production caused by impaired Akt/endothelial nitric oxide synthesis (eNOS) signaling has been demonstrated at the aorta in the presence of diabetic vascular complications, little is known regarding the details of the mechanism. We identified G-protein-coupled receptor kinase 2 (GRK2) as a critical factor in diabetic endothelial dysfunction. GRK2 plays a role in many physiological functions including regulation of G-protein-coupled receptors (GPCRs). We found that the vasculature affected by type 2 diabetes expresses high levels of GRK2, which may induce endothelial dysfunction caused by impaired Akt/eNOS signaling. GRK2 activation also induces changes in the subcellular localization of GRK2 and β-arrestin 2, a downstream protein, from the cytosol to membrane. In mouse aorta GRK2 may be, on translocation, a key negative regulator and an important regulator of β-arrestin 2/Akt/eNOS signaling, which has been implicated in diabetic endothelial dysfunction. Furthermore, in the aortic membrane of type 2 diabetic model mice under insulin stimulation, the impaired Akt/eNOS signaling was improved by a selective GRK2 inhibitor. These results suggest that in diabetes the GRK2 inhibitor ameliorates vascular endothelial dysfunction via Akt/eNOS signaling by inhibiting GRK2 activity and enhancing β-arrestin 2 translocation to the membrane under GPCR or non-GPCR stimulation, thereby contributing to blood pressure- and blood glucose-lowering effects. We propose that the GRK2 inhibitor may be a promising therapeutic target for cardiovascular complications in type 2 diabetes.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2; D003925:Diabetic Angiopathies / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2