title: G-protein-coupled receptor kinase 2 and endothelial dysfunction: molecular insights and pathophysiological mechanisms.
abstract: Smooth muscle cells (SMC) and endothelial cells are the major cell types in blood vessels. The principal function of vascular SMC in the body is to regulate blood flow and pressure through contraction and relaxation. The endothelium performs a crucial role in maintaining vascular integrity by achieving whole-organ metabolic homeostasis via the production of factors associated with vasoconstriction or vasorelaxation. In this review, we have focused on the production of nitric oxide (NO), a vasorelaxation factor. The extent of NO production represents a key marker in vascular health. A decrease in NO is capable of inducing pathological conditions associated with endothelial dysfunction, such as obesity, diabetes, cardiovascular disease, and atherosclerosis. Recent studies have strongly implicated the involvement of G-protein-coupled receptor kinase 2 (GRK2) in the progression of cardiovascular disease. Vasculature which is affected by insulin resistance and type 2 diabetes expresses high levels of GRK2, which may induce endothelial dysfunction by reducing intracellular NO. GRK2 activation also induces changes in the subcellular localization of GRK2 itself and also of β-arrestin 2, a downstream protein. In this review, we describe the pathophysiological mechanisms of insulin resistance and diabetes, focusing on the signal transduction for NO production via GRK2 and β-arrestin 2, providing novel insights into the potential field of translational investigation in the treatment of diabetic complications.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology; D002318:Cardiovascular Diseases / Q000209:etiology*; D003920:Diabetes Mellitus / Q000209:etiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000209:etiology; D015398:Signal Transduction / Q000502:physiology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; D045462:Endothelium-Dependent Relaxing Factors; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009569:Nitric Oxide; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2