Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
Heart Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
Nat Commun. 2019 Sep 12;10(1):4143. doi: 10.1038/s41467-019-12226-1.
In pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.
在肺动脉高压中，血管重构导致远端肺小动脉变窄和肺血管阻力增加。血管重构是由 DNA 损伤、恶劣的微环境中肺动脉血管细胞的存活和增殖所促进的。在这里，我们报告称，肺动脉高压患者的肺动脉平滑肌细胞中 Eyes Absent 3（EYA3）的水平升高，并且 EYA3 酪氨酸磷酸酶活性在 DNA 损伤条件下促进这些细胞的存活。携带有 EYA3 酪氨酸磷酸酶结构域失活突变的转基因小鼠对血管重构有显著的保护作用。在血管闭塞性肺动脉高压的大鼠模型中，药理学抑制 EYA3 酪氨酸磷酸酶活性可显著逆转血管重构。这些观察结果共同确定 EYA3 是一种疾病修饰靶点，其在肺动脉高压病理生理学中的功能可以通过现有的抑制剂来靶向。
