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β-Arrestin–Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

ABSTRACT: Visual Abstract Highlights • We tested the effects of a β-arrestin–biased agonist (TRV023) of the angiotensin II (AngII) type 1 receptor (AT1R), which acts as a vasodilator while not blocking cellular proliferation, compared to a balanced agonist, AngII, and an antagonist, losartan, in PAH.• In acute infusion, AngII increased right ventricular pressures while TRV023 and losartan did not. However, in chronic infusion in monocrotaline PAH rats, both TRV023 and AngII had significantly worse survival than losartan.• Both TRV023 and AngII enhanced proliferation and migration of pulmonary artery smooth muscle cells from patients with PAH.• β-arrestin-mediated AT1R signaling promotes vascular remodeling and worsens PAH, and suggests that the benefit of current PAH therapies is primarily through pulmonary vascular reverse remodeling. Summary Pulmonary arterial hypertension (PAH) is a disease of abnormal pulmonary vascular remodeling whose medical therapies are thought to primarily act as vasodilators but also may have effects on pulmonary vascular remodeling. The angiotensin II type 1 receptor (AT1R) is a G protein–coupled receptor that promotes vasoconstriction through heterotrimeric G proteins but also signals via β-arrestins, which promote cardioprotective effects and vasodilation through promoting cell survival. We found that an AT1R β-arrestin-biased agonist promoted vascular remodeling and worsened PAH, suggesting that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling in addition to their vasodilation.

SUBMITTER: Ma Z

PROVIDER: S-EPMC8617598 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rationale: Glycolytic shift is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). It remains unknown how glycolysis is increased and how increased glycolysis contributes to pulmonary vascular remodeling in PAH.Objectives: To determine whether increased glycolysis is caused by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and how PFKFB3-driven glycolysis induces vascular remodeling in PAH.Methods: PFKFB3 levels were measured in pulmonary arteries of patients and animals with PAH. Lactate levels were assessed in lungs of animals with PAH and in pulmonary artery smooth muscle cells (PASMCs). Genetic and pharmacologic approaches were used to investigate the role of PFKFB3 in PAH.Measurements and Main Results: Lactate production was elevated in lungs of PAH rodents and in platelet-derived growth factor-treated PASMCs. PFKFB3 protein was higher in pulmonary arteries of patients and rodents with PAH, in PASMCs of patients with PAH, and in platelet-derived growth factor-treated PASMCs. PFKFB3 inhibition by genetic disruption and chemical inhibitor attenuated phosphorylation/activation of extracellular signal-regulated kinase (ERK1/2) and calpain-2, and vascular remodeling in PAH rodent models, and reduced platelet-derived growth factor-induced phosphorylation/activation of ERK1/2 and calpain-2, collagen synthesis and proliferation of PASMCs. ERK1/2 inhibition attenuated phosphorylation/activation of calpain-2, and vascular remodeling in Sugen/hypoxia PAH rats, and reduced lactate-induced phosphorylation/activation of calpain-2, collagen synthesis, and proliferation of PASMCs. Calpain-2 inhibition reduced lactate-induced collagen synthesis and proliferation of PASMCs.Conclusions: Upregulated PFKFB3 mediates collagen synthesis and proliferation of PASMCs, contributing to vascular remodeling in PAH. The mechanism is through the elevation of glycolysis and lactate that results in the activation of calpain by ERK1/2-dependent phosphorylation of calpain-2.

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β-Arrestin–Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

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