Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Am J Respir Cell Mol Biol. 2011 Aug;45(2):340-7. doi: 10.1165/rcmb.2010-0316OC. Epub 2010 Nov 12.
Remodeling of the pulmonary arteries is a common feature among the heterogeneous disorders that cause pulmonary hypertension. In these disorders, the remodeled pulmonary arteries often demonstrate inflammation and an accumulation of pulmonary artery smooth muscle cells (PASMCs) within the vessels. Adipose tissue secretes multiple bioactive mediators (adipokines) that can influence both inflammation and remodeling, suggesting that adipokines may contribute to the development of pulmonary hypertension. We recently reported on a model of pulmonary hypertension induced by vascular inflammation, in which a deficiency of the adipokine adiponectin (APN) was associated with the extensive proliferation of PASMCs and increased pulmonary artery pressures. Based on these data, we hypothesize that APN can suppress pulmonary hypertension by directly inhibiting the proliferation of PASMCs. Here, we tested the effects of APN overexpression on pulmonary arterial remodeling by using APN-overexpressing mice in a model of pulmonary hypertension induced by inflammation. Consistent with our hypothesis, mice that overexpressed APN manfiested reduced pulmonary hypertension and remodeling compared with wild-type mice, despite developing similar levels of pulmonary vascular inflammation in the model. The overexpression of APN was also protective in a hypoxic model of pulmonary hypertension. Furthermore, APN suppressed the proliferation of PASMCs, and reduced the activity of the serum response factor-serum response element pathway, which is a critical signaling pathway for smooth muscle cell proliferation. Overall, these data suggest that APN can regulate pulmonary hypertension and pulmonary arterial remodeling through its direct effects on PASMCs. Hence, the activation of APN-like activity in the pulmonary vasculature may be beneficial in pulmonary hypertension.
肺血管重构是引起肺动脉高压的多种异质性疾病的共同特征。在这些疾病中，重构的肺血管通常表现为炎症和血管内肺动脉平滑肌细胞（PASMC）的积累。脂肪组织分泌多种生物活性介质（脂肪因子），这些介质可以影响炎症和重构，这表明脂肪因子可能有助于肺动脉高压的发展。我们最近报道了一种由血管炎症引起的肺动脉高压模型，其中脂肪因子脂联素（APN）的缺乏与 PASMC 的广泛增殖和肺动脉压升高有关。基于这些数据，我们假设 APN 可以通过直接抑制 PASMC 的增殖来抑制肺动脉高压。在这里，我们通过在炎症诱导的肺动脉高压模型中使用 APN 过表达小鼠，测试了 APN 过表达对肺血管重构的影响。与我们的假设一致，与野生型小鼠相比，过表达 APN 的小鼠表现出肺动脉高压和重构减轻，尽管在该模型中发展出类似水平的肺血管炎症。APN 的过表达在缺氧性肺动脉高压模型中也是保护性的。此外，APN 抑制了 PASMC 的增殖，并降低了血清反应因子-血清反应元件通路的活性，该通路是平滑肌细胞增殖的关键信号通路。总体而言，这些数据表明 APN 可以通过其对 PASMC 的直接作用来调节肺动脉高压和肺血管重构。因此，肺血管中 APN 样活性的激活可能有益于肺动脉高压。
