Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, 163319, China.
Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin, 150081, China.
Cell Death Dis. 2018 Feb 14;9(2):221. doi: 10.1038/s41419-018-0315-5.
Calcification is a major risk factor for vascular integrity. This pathological symptom and the underlying mechanisms in hypoxic pulmonary artery hypertension remain elusive. Here we report that pulmonary vascular medial calcification is elevated in pulmonary artery hypertension models as a result of an osteoblastic phenotype change of pulmonary arterial smooth muscle cells induced by hypoxia. Notably, inhibiting store-operated calcium channels significantly decreased osteoblastic differentiation and calcification of pulmonary arterial smooth muscle cells under hypoxia. We identified granzyme B, a major constituent of cytotoxic T lymphocytes/natural killer cell granules involved in apoptosis, as the main regulator of pulmonary arterial calcification. Overexpression of granzyme B blocked the mineralization through its effect on store-operated calcium channels in cultured pulmonary arterial smooth muscle cells under hypoxic conditions. Mice with overexpression of granzyme B exposed to hypoxia for 3 weeks showed attenuated vascular calcification and pathological progression of hypoxic pulmonary arterial hypertension. Our findings emphasize the central function of granzyme B in coordinating vascular calcification in hypoxic pulmonary arterial hypertension.
钙化是血管完整性的一个主要危险因素。这种病理症状及其在低氧性肺动脉高血压中的潜在机制仍不清楚。在这里，我们报告称，由于缺氧诱导的肺动脉平滑肌细胞成骨样表型改变，肺动脉高压模型中的肺血管中层钙化增加。值得注意的是，抑制储存操纵钙通道可显著减少缺氧下肺动脉平滑肌细胞的成骨分化和钙化。我们确定颗粒酶 B 是参与细胞凋亡的细胞毒性 T 淋巴细胞/自然杀伤细胞颗粒的主要成分，是肺血管钙化的主要调节因子。在缺氧条件下，过表达颗粒酶 B 通过其对储存操纵钙通道的作用阻断了培养的肺动脉平滑肌细胞的矿化。过表达颗粒酶 B 并暴露于缺氧 3 周的小鼠显示出血管钙化减轻和低氧性肺动脉高血压的病理进展减弱。我们的研究结果强调了颗粒酶 B 在协调低氧性肺动脉高血压中血管钙化中的核心作用。
