Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University, Jinzhou, China.
J Cell Mol Med. 2022 May;26(10):2819-2830. doi: 10.1111/jcmm.17295. Epub 2022 Apr 1.
Calpain-1, a calcium-activated neutral cysteine proteases, has been reported to be involved in the formation of pulmonary hypertension. HIF-1α, an oxygen-sensitive transcription factor, has been reported to activate genes involved in cell proliferation and extracellular matrix recombination. This study was designed to investigate the effect of calpain-1 in hypoxic pulmonary hypertension (HPH) and to explore whether there is a relationship between calpain-1 and HIF-1α in this disease. In the hypoxia-induced model of HPH, we found that hypoxia resulted in increased right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodelling and collagen deposition in lung tissues of mice. The levels of calpain-1 and HIF-1α were up-regulated in the lung tissues of hypoxia-treated mice and pulmonary arterial smooth muscle cells (PASMCs). Knock-out of calpain-1 restrained haemodynamic and histological changes induced by chronic hypoxia in mice, and inhibition of calpain-1 also repressed the abnormal proliferation and migration of PASMCs. Besides, knock-out or inhibition of calpain-1 suppressed hypoxia-induced expression of HIF-1α, VEGF, PCNA, TGF-β1, MMP2 and collagen I in vivo and in vitro. While inhibition of HIF-1α abolished the above effects of calpain-1. Furthermore, we found that calpain-1 mediates the expression of HIF-1α through NF-κB (P65) under hypoxia conditions. In conclusion, our results suggest that calpain-1 plays a pivotal role in hypoxia-induced pulmonary vascular remodelling and fibrosis through HIF-1α, providing a better understanding of the pathogenesis of HPH.
钙蛋白酶-1（一种钙激活的中性半胱氨酸蛋白酶）已被报道参与肺动脉高压的形成。低氧诱导因子-1α（HIF-1α）是一种氧敏感的转录因子，已被报道可激活与细胞增殖和细胞外基质重组相关的基因。本研究旨在探讨钙蛋白酶-1在低氧性肺动脉高压（HPH）中的作用，并探讨在该疾病中钙蛋白酶-1与 HIF-1α之间是否存在关系。在 HPH 的低氧诱导模型中，我们发现低氧导致小鼠右心室收缩压、右心室肥厚、肺血管重构和肺组织胶原沉积增加。低氧处理小鼠的肺组织和肺动脉平滑肌细胞（PASMCs）中钙蛋白酶-1和 HIF-1α的水平上调。钙蛋白酶-1 敲除抑制了慢性低氧诱导的小鼠血流动力学和组织学变化，抑制钙蛋白酶-1也抑制了 PASMCs 的异常增殖和迁移。此外，钙蛋白酶-1 的敲除或抑制抑制了低氧诱导的 HIF-1α、VEGF、PCNA、TGF-β1、MMP2 和胶原 I 在体内和体外的表达。而 HIF-1α 的抑制消除了钙蛋白酶-1的上述作用。此外，我们发现钙蛋白酶-1在低氧条件下通过 NF-κB（P65）介导 HIF-1α的表达。总之，我们的研究结果表明，钙蛋白酶-1通过 HIF-1α在低氧诱导的肺血管重构和纤维化中发挥关键作用，为理解 HPH 的发病机制提供了更好的认识。
