β2-Adrenoceptors and GRK2 as Potential Biomarkers in Patients With Chronic Pulmonary Regurgitation

Rodríguez‐Serrano, María; Rueda, Joaquı́n; Fuentes, Francisco Buendía; Montó, Fermí; Agüero, J.; Osa, Ana; Cano, Óscar; Martínez‐Dolz, Luis; D’Ocón, Pilar

doi:10.3389/fphar.2019.00093

Cited by 2 publications

(2 citation statements)

References 45 publications

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“…Under physiological conditions, this process occurs during embryonic development (48), pregnancy, and through the ovarian cycle, but angiogenesis can also be reactivated in a variety of pathological conditions, including cancer (49-51), RA (52)(53)(54), ischemia (55,56) and wound healing (57). The expression and function of GRK2 is tightly modulated, and its level and functionality are altered in several pathological situations (58)(59)(60). These changes contribute to EC activation and further angiogenesis in some pathologies, which has been preliminarily proven (Table 1).…”

Section: Grk2 Mediates the Regulation Of Angiogenesis In Pathological Conditionsmentioning

confidence: 99%

Potential Regulatory Roles of GRK2 in Endothelial Cell Activity and Pathological Angiogenesis

2021

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G protein-coupled receptor (GPCR) kinase 2 (GRK2) is an integrative node in many signaling network cascades. Emerging evidence indicates that GRK2 can interact with a large number of GPCRs and non-GPCR substrates in both kinase-dependent and -independent modes. Some of these pathways are associated with endothelial cell (EC) activity. The active state of ECs is a pivotal factor in angiogenesis. The occurrence and development of some inflammation-related diseases are accompanied by pathological angiogenesis, but there remains a lack of effective targeted treatments. Alterations in the expression and/or localization of GRK2 have been identified in several types of diseases and have been demonstrated to regulate the angiogenesis process in these diseases. GRK2 as a target may be a promising candidate for anti-angiogenesis therapy.

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Section: Grk2 Mediates the Regulation Of Angiogenesis In Pathological Conditionsmentioning

confidence: 99%

Potential Regulatory Roles of GRK2 in Endothelial Cell Activity and Pathological Angiogenesis

2021

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“…[9,10] In two recent studies, Sikka et al [11] and Barreto Ortiz et al [12] reported that GRK2 inhibition enhanced the photorelaxation of the pulmonary artery induced by repeated blue light exposure. Additionally, both Piao et al [13] and Rodriguez-Serrano et al [14] showed that inhibiting Gβγ–GRK2 interactions improved sensitization of the failing myocardium induced by PAH. Although GRK2 is clearly implicated in a number of processes critical to the vasculature, its role in pulmonary arterial vascular smooth muscle cells (PASMCs) and PAH has not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

GRK2–YAP signaling is implicated in pulmonary arterial hypertension development

Ye,

Deng,

et al. 2024

Chinese Medical Journal

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Background: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown. Methods: GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2 Δ SM22), and littermate controls (Grk2 flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays. Results: The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2 Δ SM22 mice compared with littermate controls. The amelioration of PH in Grk2 Δ SM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions. Conclusion: Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.

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β2-Adrenoceptors and GRK2 as Potential Biomarkers in Patients With Chronic Pulmonary Regurgitation

Cited by 2 publications

References 45 publications

Potential Regulatory Roles of GRK2 in Endothelial Cell Activity and Pathological Angiogenesis

Potential Regulatory Roles of GRK2 in Endothelial Cell Activity and Pathological Angiogenesis

GRK2–YAP signaling is implicated in pulmonary arterial hypertension development

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