Lagna Giorgio, Nguyen Peter H, Ni Weihua, Hata Akiko
Molecular Cardiology Research Institute, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111, USA.
Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L1059-67. doi: 10.1152/ajplung.00180.2006.
Germ line mutations in the bone morphogenetic protein (BMP) receptor type II (BMPRII) gene have been found in >50% of familial idiopathic pulmonary arterial hypertension (IPAH) patients and in 30% of sporadic cases of IPAH. Mutations of BMPRII occur in the extracellular ligand-binding domain, in the cytoplasmic serine/threonine kinase domain, or in the long carboxy terminus domain of unknown function. In this study, we demonstrate that BMPs promote apoptotic cell death in normal human pulmonary artery smooth muscle cells (PASMCs) by activation of caspases-3, -8, and -9, cytochrome c release, and downregulation of Bcl-2. Normal PASMCs expressing a kinase domain mutant or a carboxy-terminal domain deletion mutant of BMPRII identified in IPAH patients are resistant to BMP-mediated apoptosis. This dominant-negative effect may act in heterozygous patients and lead to the development of the pulmonary vascular medial hypertrophy found in IPAH patients. Our study also demonstrates an essential role of the carboxy terminus domain of BMPRII in the activation of the apoptotic signaling cascade.
在超过50%的家族性特发性肺动脉高压（IPAH）患者以及30%的散发性IPAH病例中，已发现骨形态发生蛋白（BMP）II型受体（BMPRII）基因的种系突变。BMPRII突变发生在细胞外配体结合域、细胞质丝氨酸/苏氨酸激酶域或功能未知的长羧基末端域。在本研究中，我们证明BMPs通过激活半胱天冬酶-3、-8和-9、细胞色素c释放以及下调Bcl-2来促进正常人肺动脉平滑肌细胞（PASMCs）的凋亡性细胞死亡。表达在IPAH患者中鉴定出的BMPRII激酶域突变体或羧基末端域缺失突变体的正常PASMCs对BMP介导的凋亡具有抗性。这种显性负效应可能在杂合患者中起作用，并导致IPAH患者出现肺血管中层肥厚。我们的研究还证明了BMPRII羧基末端域在凋亡信号级联激活中的重要作用。
