Song Yanli, Coleman Laura, Shi Jianru, Beppu Hideyuki, Sato Kaori, Walsh Kenneth, Loscalzo Joseph, Zhang Ying-Yi
Cardiovascular Division, Dept. of Medicine, Brigham and Women's Hosiptal and Harvard Medical School, 77 Ave. Louis Pasteur, NRB 630, Boston, MA 02115, USA.
Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H677-90. doi: 10.1152/ajpheart.91519.2007. Epub 2008 Jun 13.
Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2(+/-)) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2(+/-) mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replication-deficient adenovirus expressing 5-lipoxygenase (MCT+Ad5LO). After the challenge (1 wk), BMPR2(+/-) mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wild-type mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2(+/-) lungs at 2 wk after the challenge and became severe at 3 wk. Marked perivascular infiltration of T cells, B cells, and macrophages was associated with the remodeled vessels. Real-time PCR analysis showed that the expression of six endothelial cell markers in lung tissue was decreased to 20-40% of original levels at 1 wk after the challenge in both BMPR2(+/-) and wild-type mice and largely recovered in wild-type (50-80%) but not BMPR2(+/-) lungs (30-50%) at 3 wk after the challenge. Macrophage inflammatory protein-1alpha and fractalkine receptor expression doubled in BMPR2(+/-) compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-beta receptors, in the challenged BMPR2(+/-) and wild-type lungs showed a similar pattern of expression as that of endothelial markers. Apoptotic responses at 1 wk after MCT and Ad5LO challenge were also significantly greater in the BMPR2(+/-) lungs than the wild-type lungs. These data show that BMPR2(+/-) mice are more sensitive to MCT+Ad5LO-induced pulmonary hypertension than wild-type mice. Greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension.
杂合性骨形态发生蛋白受体-II基因敲除（BMPR2(+/-)）小鼠具有与某些特发性肺动脉高压患者相似的遗传特征。为了研究肺内皮损伤对BMPR2(+/-)小鼠的影响，我们对小鼠进行两次注射野百合碱并气管内滴注表达5-脂氧合酶的复制缺陷型腺病毒（MCT+Ad5LO）。刺激后（1周），BMPR2(+/-)小鼠右心室收缩压翻倍，高于野生型小鼠，并且在心力衰竭发生前持续升高3周。刺激后2周，BMPR2(+/-)小鼠肺组织中小肺动脉出现肌化和增厚，3周时变得严重。T细胞、B细胞和巨噬细胞显著的血管周围浸润与血管重塑有关。实时PCR分析显示，在刺激后1周，BMPR2(+/-)小鼠和野生型小鼠肺组织中六种内皮细胞标志物的表达均降至原始水平的20%-40%，在刺激后3周，野生型小鼠（50%-80%）肺组织中表达大部分恢复，但BMPR2(+/-)小鼠肺组织中（30%-50%）未恢复。与野生型肺相比，BMPR2(+/-)小鼠肺中巨噬细胞炎性蛋白-1α和趋化因子受体表达翻倍。在受刺激的BMPR2(+/-)小鼠和野生型小鼠肺中，I型和II型BMP受体的表达，但不包括转化生长因子-β受体的表达，显示出与内皮标志物相似的表达模式。MCT和Ad5LO刺激后1周，BMPR2(+/-)小鼠肺中的凋亡反应也明显高于野生型小鼠肺。这些数据表明，BMPR2(+/-)小鼠比野生型小鼠对MCT+Ad5LO诱导的肺动脉高压更敏感。更大程度的内皮损伤和增强的炎症反应可能是敏感性的潜在原因，并且可能与BMPR2杂合性协同作用以促进持续性肺动脉高压的发展。
