Kosair Charities Pediatric Heart Research Program, Cardiovascular Innovation Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky.
Department of Anesthesiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Am J Physiol Heart Circ Physiol. 2020 Apr 1;318(4):H853-H866. doi: 10.1152/ajpheart.00321.2019. Epub 2020 Feb 28.
Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies. Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.
右心室（RV）功能障碍是肺动脉高压（PAH）患者死亡的主要决定因素，尽管炎症在 PAH 中具有致病性，但关于 RV 炎症在 PAH 中的作用的信息有限。萝卜硫素（SFN）是一种有效的 Nrf2 激活剂，具有显著的抗炎作用，并在临床前糖尿病模型中促进心脏保护。因此，我们假设 SFN 可能在减少 RV 和肺炎症和损伤方面在 PAH 小鼠模型中发挥类似作用。我们使用 SU5416 和 10%缺氧（SuHx）在雄性小鼠中诱导 PAH，随机分为 SFN 每日剂量为 0.5mg/kg，每周 5 天，共 4 周，或给予载体对照。通过经胸超声心动图在 PAH 诱导期间对特定心室功能进行特征描述。在 4 周时，我们测量 RV 压力以及相关的组织学和蛋白质及基因表达测量值。SuHx 诱导进行性 RV，但不是 LV，舒张和收缩功能障碍以及 RV 和肺重塑、纤维化和炎症。SFN 预防 SuHx 诱导的 RV 功能障碍和重塑，减少 RV 炎症和纤维化，上调 Nrf2 表达及其下游基因 NQO1，并减少炎症介质富含亮氨酸重复和吡咯烷域包含 3（NLRP3）。SFN 还减少 SuHx 诱导的肺血管重塑、炎症和纤维化。SFN 本身对心脏或肺部没有影响。因此，SFN 可减轻或预防 SuHx 诱导的 RV 和肺功能障碍、炎症和纤维化，支持进一步研究以调查 SFN 和 Nrf2 及 NLRP3 途径在临床前和临床 PAH 研究中的作用的原理。该小鼠模型（SU5416+缺氧）中的肺动脉高压（PAH）与 RV 舒张和收缩功能的早期变化有关。SU5416+缺氧模型中的 RV 和肺损伤与纤维化、炎症和氧化应激标志物有关。SFN 单独使用 4 周对小鼠心脏或肺部没有影响。SFN 减轻或预防 SUF5416+缺氧模型中的 RV 和肺损伤，表明 Nrf2 可能是预防或逆转 PAH 的策略的候选靶点。
