Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.
Granzyme B deficiency promotes osteoblastic differentiation and calcification of vascular smooth muscle cells in hypoxic pulmonary hypertension.
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颗粒酶 B 缺乏促进缺氧性肺动脉高压中的成骨细胞分化和血管平滑肌细胞钙化。
DOI：
10.1038/s41419-018-0315-5
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发表时间：
2018-02-14
影响因子：
9
通讯作者：
Zhu D
中科院分区：
文献类型：
--
作者：
Mao M;Zhang M;Ge A;Ge X;Gu R;Zhang C;Fu Y;Gao J;Wang X;Liu Y;Zhu D
钙化是影响血管完整性的主要危险因素。低氧肺动脉高压的病理症状及其机制尚不清楚。在这里，我们报道肺动脉高压模型中，肺动脉平滑肌细胞在缺氧诱导下发生成骨表型改变，导致肺血管内侧钙化升高。值得注意的是，抑制储运钙通道可显著降低缺氧条件下肺动脉平滑肌细胞的成骨细胞分化和钙化。我们发现颗粒酶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，是肺动脉钙化的主要调节剂。在缺氧条件下，颗粒酶B的过表达通过其对培养肺动脉平滑肌细胞储运钙通道的影响来阻断矿化。颗粒酶B过表达小鼠缺氧3周后血管钙化减弱，低氧肺动脉高压病理进展。我们的研究结果强调颗粒酶B在协调缺氧肺动脉高压血管钙化中的中心作用。
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.
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影响因子：
9.3
作者：
Leopold JA
通讯作者：
Leopold JA
影响因子：
3.7
作者：
Boivin WA;Shackleford M;Vanden Hoek A;Zhao H;Hackett TL;Knight DA;Granville DJ
通讯作者：
Granville DJ
影响因子：
19.6
作者：
Chen, Neal X.;Kircelli, Fatih;Moe, Sharon M.
通讯作者：
Moe, Sharon M.
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1164/rccm.201607-1515pp
发表时间：
2017-03-01
影响因子：
24.7
作者：
Bonnet, Sebastien;Provencher, Steeve;Humbert, Marc
通讯作者：
Humbert, Marc