Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, Ministry of Education, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University, Chongqing, China.
Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
PLoS One. 2014 Mar 19;9(3):e83895. doi: 10.1371/journal.pone.0083895. eCollection 2014.
Hypoxia induced pulmonary hypertension (HPH) represents a complex pathology that involves active vascular remodeling, loss of vascular tone, enhanced pulmonary inflammation, and increased deposition of extracellular matrix proteins. Megakaryocytic leukemia 1 (MKL1) is a transcriptional regulator known to influence cellular response to stress signals in the vasculature. We report here that in response to chronic hypobaric hypoxia, MKL1 expression was up-regulated in the lungs in rats. Short hairpin RNA (shRNA) mediated depletion of MKL1 significantly ameliorated the elevation of pulmonary arterial pressure in vivo with a marked alleviation of vascular remodeling. MKL1 silencing also restored the expression of NO, a key vasoactive molecule necessary for the maintenance of vascular tone. In addition, hypoxia induced pulmonary inflammation was dampened in the absence of MKL1 as evidenced by normalized levels of pro-inflammatory cytokines and chemokines as well as reduced infiltration of pro-inflammatory immune cells in the lungs. Of note, MKL1 knockdown attenuated fibrogenesis in the lungs as indicated by picrosirius red staining. Finally, we demonstrate that MKL1 mediated transcriptional activation of type I collagen genes in smooth muscle cells under hypoxic conditions. In conclusion, we data highlight a previously unidentified role for MKL1 in the pathogenesis of HPH and as such lay down groundwork for future investigation and drug development.
低氧诱导性肺动脉高压（HPH）是一种复杂的病理学，涉及到活跃的血管重塑、血管张力丧失、肺炎症增强以及细胞外基质蛋白的沉积增加。巨核细胞白血病 1（MKL1）是一种转录调节剂，已知其能影响血管对应激信号的细胞反应。我们在此报告，在慢性低压缺氧的情况下，MKL1 在大鼠肺部的表达上调。短发夹 RNA（shRNA）介导的 MKL1 耗竭显著改善了体内肺动脉压力的升高，并明显减轻了血管重塑。MKL1 沉默还恢复了 NO 的表达，NO 是维持血管张力所必需的关键血管活性分子。此外，MKL1 的缺失减轻了低氧诱导的肺炎症，表现为促炎细胞因子和趋化因子的水平正常化，以及肺内促炎免疫细胞的浸润减少。值得注意的是，MKL1 敲低可减轻肺纤维化，如天狼猩红染色所示。最后，我们证明 MKL1 在低氧条件下介导平滑肌细胞中 I 型胶原基因的转录激活。总之，我们的数据突出了 MKL1 在 HPH 发病机制中的一个以前未被识别的作用，为未来的研究和药物开发奠定了基础。
