Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe-University, Frankfurt am Main, and German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany.
University of Giessen and Marburg Lung Center, Justus-Liebig-University Giessen and German Center for Lung Research (DZL), Germany.
Cardiovasc Res. 2016 Aug 1;111(3):184-93. doi: 10.1093/cvr/cvw065. Epub 2016 Mar 24.
Pulmonary hypertension is a progressive disease with poor prognosis, characterized by pathological inward remodelling and loss of patency of the lung vasculature. The right ventricle is co-affected by pulmonary hypertension, which triggers events such as hypoxia and/or increased mechanical load. Initially the right ventricle responds with 'adaptive' hypertrophy, which is often rapidly followed by 'maladaptive' changes leading to right heart decompensation and failure, which is the ultimate cause of death.
We report here that miR-223 is expressed in the murine lung and right ventricle at higher levels than in the left ventricle. Moreover, lung and right-ventricular miR-223 levels were markedly down-regulated by hypoxia. Correspondingly, increasing right-ventricular load by pulmonary artery banding, induced right-ventricular ischaemia, and the down-regulation of miR-223. Lung and right ventricle miR-223 down-regulation were linked with increased expression of the miR-223 target; insulin-like growth factor-I receptor (IGF-IR) and IGF-I downstream signalling. Similarly, miR-223 was decreased and IGF-IR increased in human pulmonary hypertension. Notably in young mice, miR-223 overexpression, the genetic inactivation or pharmacological inhibition of IGF-IR, all attenuated right-ventricular hypertrophy and improved right heart function under conditions of hypoxia or increased afterload.
These findings highlight the early role of pulmonary and right-ventricular miR-223 and the IGF-IR in the right heart failure programme initiated by pulmonary hypoxia and increased mechanical load and may lead to the development of novel therapeutic strategies that target the development of PH and right heart failure.
肺动脉高压是一种预后不良的进行性疾病，其特征为肺血管病理性重构和管腔闭塞。右心室受肺动脉高压的影响，继而引发缺氧和/或机械负荷增加等事件。起初，右心室会出现“适应性”肥厚，随后迅速出现“失代偿性”改变，导致右心衰竭和衰竭，这是死亡的最终原因。
我们在此报告，miR-223 在小鼠的肺部和右心室中的表达水平高于左心室。此外，低氧显著下调肺部和右心室 miR-223 的水平。相应地，通过肺动脉结扎增加右心室负荷，诱导右心室缺血，并下调 miR-223。肺和右心室 miR-223 的下调与 miR-223 靶标；胰岛素样生长因子-I 受体（IGF-IR）和 IGF-I 下游信号的表达增加有关。同样，miR-223 在人类肺动脉高压中减少，IGF-IR 增加。值得注意的是，在年轻小鼠中，miR-223 过表达、IGF-IR 的基因失活或药理学抑制，均能在低氧或后负荷增加的情况下减轻右心室肥厚并改善右心功能。
这些发现强调了肺和右心室 miR-223 和 IGF-IR 在由肺缺氧和机械负荷增加引起的右心衰竭计划中的早期作用，并可能导致开发针对 PH 和右心衰竭发展的新治疗策略。
