Pulmonary arterial hypertension (PAH) is a progressive disease characterised by pro-proliferative and anti-apoptotic phenotype in vascular cells, leading to pulmonary vascular remodelling and right heart failure. Peptidyl-prolyl cis/trans isomerase, NIMA interacting 1 (Pin1), a highly conserved enzyme, which binds to and catalyses the isomerisation of specific phosphorylated Ser/Thr-Pro motifs, acts as a molecular switch in multiple coordinated cellular processes. We hypothesised that Pin1 plays a substantial role in PAH, and its inhibition with a natural organic compound, Juglone, would reverse experimental pulmonary hypertension.

We demonstrated that the expression of Pin1 was markedly elevated in experimental pulmonary hypertension (i.e. hypoxia-induced mouse and Sugen/hypoxia-induced rat models) and pulmonary arterial smooth muscle cells of patients with clinical PAH. In vitro Pin1 inhibition by either Juglone treatment or short interfering RNA knockdown resulted in an induction of apoptosis and decrease in proliferation of human pulmonary vascular cells. Stimulation with growth factors induced Pin1 expression, while its inhibition reduced the activity of numerous PAH-related transcription factors, such as hypoxia-inducible factor (HIF)-α and signal transducer and activator of transcription (STAT). Juglone administration lowered pulmonary vascular resistance, enhanced right ventribular function, improved pulmonary vascular and cardiac remodelling in the Sugen/hypoxia rat model of PAH and the chronic hypoxia-induced pulmonary hypertension model in mice.

Our study demonstrates that targeting of Pin1 with small molecule inhibitor, Juglone, might be an attractive future therapeutic strategy for PAH and right heart disease secondary to PAH.

肺动脉高压（PAH）是一种进行性疾病，其特征是血管细胞的促增殖和抗凋亡表型，导致肺血管重塑和右心衰竭。肽基脯氨酰顺/反异构酶，NIMA 相互作用 1 (Pin1)，一种高度保守的酶，可结合并催化特定磷酸化 Ser/Thr-Pro 基序的异构化，在多个协调细胞过程中充当分子开关。我们假设 Pin1 在 PAH 中发挥重要作用，用天然有机化合物 Juglone 抑制它可以逆转实验性肺动脉高压。

我们证明Pin1的表达在实验性肺动脉高压（即缺氧诱导的小鼠和Sugen/缺氧诱导的大鼠模型）和临床PAH患者的肺动脉平滑肌细胞中显着升高。在体外，通过胡桃酮处理或短干扰 RNA 敲低来抑制 Pin1 会导致人肺血管细胞凋亡的诱导和增殖的减少。生长因子的刺激诱导 Pin1 表达，而其抑制则降低了许多 PAH 相关转录因子的活性，例如缺氧诱导因子 (HIF)-α 以及信号转导子和转录激活子 (STAT)。在PAH的Sugen/缺氧大鼠模型和小鼠慢性缺氧诱导的肺动脉高压模型中，胡桃醌给药降低了肺血管阻力，增强了右心室功能，改善了肺血管和心脏重塑。

我们的研究表明，用小分子抑制剂 Juglone 靶向 Pin1 可能是治疗 PAH 和继发于 PAH 的右心疾病的一种有吸引力的未来治疗策略。