Yu Lunyin, Quinn Deborah A, Garg Hari G, Hales Charles A
Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch-148, Boston, MA 02114-2696, USA.
Am J Respir Crit Care Med. 2008 Jun 1;177(11):1276-84. doi: 10.1164/rccm.200710-1522OC. Epub 2008 Feb 28.
Our previous studies found that Na(+)/H(+) exchanger (NHE) activity played an essential role in pulmonary artery smooth muscle cell (PASMC) proliferation and in the development of hypoxia-induced pulmonary hypertension and vascular remodeling. Other investigators recently observed increased expression of the NHE isoform 1 (NHE1) gene in rodents with pulmonary hypertension induced by hypoxia. However, a causal role for the NHE1 gene in pulmonary hypertension has not been determined.
To determine the causal role of the NHE1 gene in pulmonary hypertension and vascular remodeling.
We used NHE1-null mice to define the role of the NHE1 gene in the development of pulmonary hypertension and remodeling induced by hypoxia and to delineate the NHE1 regulatory pathway.
After 2 weeks of exposure to hypoxia, in contrast to wild-type hypoxic littermates, there was no significant increase in right ventricular systolic pressure, in the ratio of right ventricular to left ventricular plus septal weight [RV/(LV + S)], or in medial wall thickness of the pulmonary arterioles in homozygous mice (NHE1(-/-)). There was a significant decrease in Rho kinase (ROCK1 and ROCK2) expression, accompanied by an increase in p27 expression in NHE1(-/-) mice.
Our study demonstrated that deficiency of the NHE1 gene prevented the development of hypoxia-induced pulmonary hypertension and vascular remodeling in mice and revealed a novel regulatory pathway associated with NHE1 signaling.
我们之前的研究发现，钠氢交换体（NHE）活性在肺动脉平滑肌细胞（PASMC）增殖以及低氧诱导的肺动脉高压和血管重塑的发展过程中起着至关重要的作用。其他研究人员最近观察到，在低氧诱导的肺动脉高压啮齿动物中，NHE同工型1（NHE1）基因的表达增加。然而，NHE1基因在肺动脉高压中的因果作用尚未确定。
确定NHE1基因在肺动脉高压和血管重塑中的因果作用。
我们使用NHE1基因敲除小鼠来确定NHE1基因在低氧诱导的肺动脉高压和重塑发展中的作用，并描绘NHE1调控途径。
暴露于低氧环境2周后，与野生型低氧同窝小鼠相比，纯合小鼠（NHE1(-/-)）的右心室收缩压、右心室与左心室加室间隔重量之比[RV/(LV + S)]或肺小动脉中膜厚度均无显著增加。NHE1(-/-)小鼠中Rho激酶（ROCK1和ROCK2）表达显著降低，同时p27表达增加。
我们的研究表明，NHE1基因缺陷可阻止小鼠低氧诱导的肺动脉高压和血管重塑的发展，并揭示了一条与NHE1信号传导相关的新调控途径。
