肺动脉高压
缺氧(环境)
基因剔除小鼠
肺动脉
受体
内科学
原位杂交
内分泌学
医学
心脏病学
病理
生物
化学
氧气
基因表达
生物化学
基因
有机化学
作者
Catherine D’Addario,Shun Matsumura,A. Kitagawa,Gregg M. Lainer,Frank Zhang,Melinee D’silva,M. Firoze Khan,Ghezal Froogh,Artiom Gruzdev,Darryl C. Zeldin,Michal Laniado Schwartzman,Sachin A. Gupte
标识
DOI:10.1016/j.vph.2023.107235
摘要
Pulmonary hypertension (PH) is a multifactorial disease with a poor prognosis and inadequate treatment options. We found two-fold higher expression of the orphan G-Protein Coupled Receptor 75 (GPR75) in leukocytes and pulmonary arterial smooth muscle cells from idiopathic PH patients and from lungs of C57BL/6 mice exposed to hypoxia. We therefore postulated that GPR75 signaling is critical to the pathogenesis of PH.To test this hypothesis, we exposed global (Gpr75-/-) and endothelial cell (EC) GPR75 knockout (EC-Gpr75-/-) mice and wild-type (control) mice to hypoxia (10% oxygen) or normal atmospheric oxygen for 5 weeks. We then recorded echocardiograms and performed right heart catheterizations.Chronic hypoxia increased right ventricular systolic and diastolic pressures in wild-type mice but not Gpr75-/- or EC-Gpr75-/- mice. In situ hybridization and qPCR results revealed that Gpr75 expression was increased in the alveoli, airways and pulmonary arteries of mice exposed to hypoxia. In addition, levels of chemokine (CC motif) ligand 5 (CCL5), a low affinity ligand of GPR75, were increased in the lungs of wild-type, but not Gpr75-/-, mice exposed to hypoxia, and CCL5 enhanced hypoxia-induced contraction of intra-lobar pulmonary arteries in a GPR75-dependent manner. Gpr75 knockout also increased pulmonary cAMP levels and decreased contraction of intra-lobar pulmonary arteries evoked by endothelin-1 or U46619 in cAMP-protein kinase A-dependent manner.These results suggest GPR75 has a significant role in the development of hypoxia-induced PH.
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