2019 年 69 巻 1-4 号 p. 146-154
Background: Endothelin（ET）is a strong vasoconstrictor that plays important roles in the pathogenesis and progression of cardiovascular remodeling. ET receptor（ET-R）antagonists have recently become established as a drug essential for treating pulmonary arterial hypertension（PAH）.
β-arrestin was originally identified as a regulator of G-protein coupled receptor recycling, but it recently became apparent that
β-arrestins act as scaffolds in their own signaling pathway. In this study, we examined the role of
β-arrestin in ET-R signaling and explored its possible role in the pathogenesis of PAH.
Methods and Results: The knockdown of
β-arrestin1 or
β-arrestin2 in human kidney embryonic 293 cells resulted in enhanced extracellular signal-regulated kinase（ERK）1/2 phosphorylation in response to ET. Confocal microscopy showed that, in the absence of stimulation, transiently transfected green fluorescent protein-tagged epidermal growth factor receptors（EGFRs）were located on the plasma membrane, whereas they were internalized in response to ET, as shown by their redistribution into cellular aggregates. Pretreatment with Ro318425（a protein kinase C inhibitor）or AG1478（an EGFR antagonist）suppressed ERK1/2 phosphorylation in response to ET.
Conclusions: β-arrestins and EGFR transactivation are involved in ET-R signaling. These new insights may contribute to elucidating further layers in the pathogenesis of PAH.
