Iloprost reverses established fibrosis in experimental right ventricular failure
Iloprost reverses established fibrosis in experimental right ventricular failure
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DOI：
10.1183/09031936.00188013
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发表时间：
2015-02-01
影响因子：
24.3
通讯作者：
Voelkel, Norbert F.
中科院分区：
文献类型：
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作者：
Gomez-Arroyo, Jose;Sakagami, Masahiro;Voelkel, Norbert F.
前列环素及其类似物可改善肺动脉高压（PAH）患者的心输出量和功能能力；然而，其根本机制尚不完全清楚。我们假设前列腺素类药物对右心室 (RV) 具有与负荷无关的有益作用。大鼠单次注射 SU5416，然后暴露于缺氧 4 周，可诱导血管闭塞性 PAH 和 RV 衰竭。确认右心室功能障碍和PAH后，将大鼠随机分配至0.1μg.kg(-1)雾化伊洛前列素或不含药物的载体，每天3次，持续2周。在伊洛前列素/载体治疗之前和之后评估右心室功能和跑步机跑步时间。肺动脉束带大鼠术后8周接受治疗，以允许明显的右心室肥厚。吸入伊洛前列素显着改善三尖瓣环平面收缩期偏移并增加运动能力，而平均肺动脉压和闭塞肺血管的百分比保持不变。在 SU5416/缺氧和肺动脉带状大鼠中，用伊洛前列素治疗的大鼠的 RV 胶原沉积、前胶原 mRNA 水平和结缔组织生长因子表达显着减少。在体外，用伊洛前列素处理的心脏成纤维细胞显示，转化生长因子 (TGF)-β1 诱导的结缔组织生长因子表达以蛋白激酶 A 依赖性方式减少。伊洛前列素降低 TGF-β1 诱导的前胶原 mRNA 表达以及心脏成纤维细胞的活化和迁移。伊洛前列素显着诱导金属蛋白酶 9 基因表达和活性，并增加与胶原蛋白降解相关的自噬基因的表达。吸入伊洛前列素可通过阻止胶原蛋白合成和增加胶原蛋白更新来部分改善右心室功能并逆转已形成的右心室纤维化。
Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV).Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 mu g.kg(-1) nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy.Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-beta 1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-beta 1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation.Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover.