Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH 43210, USA.
Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Int J Mol Sci. 2022 May 12;23(10):5426. doi: 10.3390/ijms23105426.
Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.
前列环素类似物是肺动脉高压（PAH）最有效和广泛使用的治疗方法之一。然而，目前尚不清楚它们是否通过右心室（RV）心肌特异性机制提供保护。此外，前列环素类似物在严重 PAH 模型中的应用尚未得到充分测试。为了进一步确定前列环素的潜在反应，使用前列环素类似物曲前列尼尔在一种类似于人类疾病的严重 PAH 的 SuCH 慢性缺氧（SuCH）模型的临床前大鼠中进行了研究。雄性 Sprague-Dawley 大鼠植入含有载体或曲前列尼尔的渗透泵，同时注射 Sugen（SU5416），并暴露于 3 周的低氧环境，随后是 3 周的常氧环境。使用压力-容积环评估 RV 功能，通过重量评估肥厚。为了确定 RV 内改变的机制，使用组织样本进行定制的 RNA 阵列分析、组织学染色以及蛋白和转录本水平的确认分析。曲前列尼尔显著降低了 SuCH 相关的 RV 肥厚，并降低了 RV 收缩压、肺动脉平均压（mPAP）和右心房压（RAP）的升高。前列环素治疗与 RV stroke work、心室压力最大变化率（max dP/dt）和收缩指数的改善相关，并且几乎完全逆转了 SuCH 相关的 RV 收缩末期弹性增加，这表明前列环素治疗通过负荷独立的方式改善了 RV 收缩性内在收缩力。对 RV 组织的分析显示，心脏线粒体呼吸和 ATP 生成没有变化。然而，定制的 RNA 阵列分析显示，曲前列尼尔治疗可改善 SuCH 相关的新发现的 TBX20 以及纤维化标志物胶原 1α1 和胶原 3α1 的增加。总的来说，我们的数据支持在严重 PAH 中给予前列环素后，后负荷降低和 RV 功能的负荷独立改善，这些变化似乎与 RV 纤维化反应的改善相关。
