Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, 510515, People's Republic of China.
Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
Cell Biol Toxicol. 2024 Feb 13;40(1):13. doi: 10.1007/s10565-024-09849-6.
Nuclear protein 1 (Nupr1) is a multifunctional stress-induced protein involved in the regulation of tumorigenesis, apoptosis, and autophagy. However, its role in pulmonary hypertension (PH) after METH exposure remains unexplored. In this study, we aimed to investigate whether METH can induce PH and describe the role and mechanism of Nupr1 in the development of PH.
Mice were made to induce pulmonary hypertension (PH) upon chronic intermittent treatment with METH. Their right ventricular systolic pressure (RVSP) was measured to assess pulmonary artery pressure. Pulmonary artery morphometry was determined by H&E staining and Masson staining. Nupr1 expression and function were detected in human lungs, mice lungs exposed to METH, and cultured pulmonary arterial smooth muscle cells (PASMCs) with METH treatment. Our results showed that chronic intermittent METH treatment successfully induced PH in mice. Nupr1 expression was increased in the cultured PASMCs, pulmonary arterial media from METH-exposed mice, and METH-ingested human specimens compared with control. Elevated Nupr1 expression promoted PASMC phenotype change from contractile to synthetic, which triggered pulmonary artery remodeling and resulted in PH formation. Mechanistically, Nupr1 mediated the opening of store-operated calcium entry (SOCE) by activating the expression of STIM1, thereby promoting Ca influx and inducing phenotypic conversion of PASMCs.
Nupr1 activation could promote Ca influx through STIM1-mediated SOCE opening, which promoted METH-induced pulmonary artery remodeling and led to PH formation. These results suggested that Nupr1 played an important role in METH-induced PH and might be a potential target for METH-related PH therapy.
核蛋白 1（Nupr1）是一种多功能应激诱导蛋白，参与肿瘤发生、细胞凋亡和自噬的调节。然而，其在 METH 暴露后肺动脉高压（PH）中的作用尚未被探索。在本研究中，我们旨在研究 METH 是否可以诱导 PH，并描述 Nupr1 在 PH 发展中的作用和机制。
用慢性间歇性 METH 处理来诱导小鼠发生肺动脉高压（PH）。通过右心室收缩压（RVSP）来测量肺动脉压，以评估肺动脉压力。通过 H&E 染色和 Masson 染色来确定肺动脉形态计量学。检测了人类肺、暴露于 METH 的小鼠肺和用 METH 处理的培养肺动脉平滑肌细胞（PASMCs）中的 Nupr1 表达和功能。结果表明，慢性间歇性 METH 处理成功地在小鼠中诱导了 PH。与对照组相比，在培养的 PASMCs、暴露于 METH 的小鼠肺动脉中膜和 METH 摄入的人类标本中，Nupr1 表达增加。升高的 Nupr1 表达促进了 PASMC 从收缩型向合成型表型的改变，引发了肺动脉重构，导致 PH 的形成。机制上，Nupr1 通过激活 STIM1 的表达来介导储存操作钙内流（SOCE）的开放，从而促进 Ca 内流并诱导 PASMC 表型转换。
Nupr1 的激活可以通过 STIM1 介导的 SOCE 开放来促进 Ca 内流，从而促进 METH 诱导的肺动脉重构并导致 PH 的形成。这些结果表明，Nupr1 在 METH 诱导的 PH 中发挥重要作用，可能是 METH 相关 PH 治疗的潜在靶点。
