1 Universities of Giessen and Marburg Lung Center, Giessen, Germany.
2 Excellence Cluster Cardio-Pulmonary System, Giessen, Germany.
Am J Respir Cell Mol Biol. 2019 Mar;60(3):346-356. doi: 10.1165/rcmb.2018-0069OC.
The ability of the right ventricle to compensate pressure overload determines survival in pulmonary arterial hypertension (PAH). Nitric oxide (NO) reduces the right ventricular afterload through pulmonary vasodilation, but excessive NO amounts cause oxidative stress. Oxidative stress drives remodeling of pulmonary arteries and the right ventricle. In the present study, we hypothesized that nitric oxide synthase 2 (NOS2) induction leads to excessive NO amounts that contribute to oxidative stress and impair right ventricular adaptation to PAH. We used a surgical pulmonary artery banding (PAB) mouse model in which right ventricular dysfunction and remodeling occur independently of changes in the pulmonary vasculature. Three weeks after PAB, NOS2 expression was increased twofold in the hypertrophied right ventricle on transcript and protein levels together with increased NO production. Histomorphology localized NOS2 in interstitial and perivascular cardiac fibroblasts after PAB, which was confirmed by cell isolation experiments. In the hypertrophied right ventricle, NOS2 induction was accompanied by an increased formation of reactive oxidants blocked by ex vivo NOS inhibition. We show that reactive oxidant formation in the hypertrophied right ventricle is in part NOS2 dependent (in NOS2-deficient mice [NOS2]). Lack of NOS2 induction prevented superoxide scavenging and decreased reactive oxidant formation. Functional measures of cardiac function by noninvasive echocardiography together with intracardiac catheterization revealed no differences in heart function between both genotypes after PAB. However, reduced NO and reactive oxidant formation in the hypertrophied right ventricle of NOS2 mice was linked to reduced collagen accumulation through reduced collagen deposition from the cardiac fibroblast. Together, our data demonstrate a profibrotic role for NOS2 induction in the hypertrophied right ventricle.
右心室代偿压力超负荷的能力决定了肺动脉高压（PAH）患者的生存。一氧化氮（NO）通过肺血管舒张减轻右心室后负荷，但过多的 NO 会导致氧化应激。氧化应激会导致肺血管和右心室重构。在本研究中，我们假设诱导一氧化氮合酶 2（NOS2）会导致过多的 NO 产生，从而导致氧化应激，并损害右心室对 PAH 的适应能力。我们使用了一种外科肺动脉结扎（PAB）小鼠模型，其中右心室功能障碍和重构发生在肺血管变化之外。PAB 后 3 周，肥厚的右心室中转录本和蛋白质水平的 NOS2 表达增加了两倍，同时 NO 产量增加。组织形态学将 PAB 后 NOS2 定位于间质和血管周围的心肌成纤维细胞中，细胞分离实验对此进行了验证。在肥厚的右心室中，NOS2 诱导伴随着活性氧的形成增加，这种形成可被体外 NOS 抑制阻断。我们表明，肥厚的右心室中活性氧的形成部分依赖于 NOS2（在 NOS2 缺陷型小鼠[NOS2-/-]中）。NOS2 诱导的缺失会阻止超氧化物的清除并减少活性氧的形成。非侵入性超声心动图和心内导管插入术的心脏功能的功能测量表明，PAB 后两种基因型之间的心脏功能没有差异。然而，NOS2 小鼠肥厚右心室中 NO 和活性氧形成的减少与胶原沉积减少有关，从而减少了心肌成纤维细胞的胶原沉积。总之，我们的数据表明，NOS2 诱导在肥厚的右心室中具有促纤维化作用。
