Semenza Gregg L
Institute for Cell Engineering, Department of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Investig Med. 2016 Feb;64(2):361-3. doi: 10.1097/JIM.0000000000000206. Epub 2016 Jan 11.
When tissue perfusion is impaired, the resulting reduction in O2 availability activates hypoxia-inducible factor 1 (HIF-1), which mediates increased transcription of genes encoding multiple angiogenic factors including vascular endothelial growth factor, stromal-derived factor 1, placental growth factor, and angiopoietins, leading to the mobilization of bone marrow-derived angiogenic cells, increased angiogenesis, and arterial remodeling. These HIF- 1-dependent responses are impaired by aging or loss of function mutations at the locus encoding the HIF-1α subunit. in mouse models of limb ischemia and lung transplant rejection, the augmentation of HIF-1 activity by gene therapy or chemical inducers was associated with maintenance of tissue perfusion that prevented limb amputation and allograft rejection, respectively. Thus, targeting HIF-1 may be of therapeutic benefit in these clinical contexts and others in which impaired tissue perfusion plays a role in disease pathogenesis.
当组织灌注受损时，由此导致的氧供应减少会激活缺氧诱导因子1（HIF-1），它介导编码多种血管生成因子的基因转录增加，这些因子包括血管内皮生长因子、基质细胞衍生因子1、胎盘生长因子和血管生成素，从而导致骨髓来源的血管生成细胞动员、血管生成增加和动脉重塑。这些依赖HIF-1的反应会因衰老或HIF-1α亚基编码基因座的功能丧失突变而受损。在肢体缺血和肺移植排斥反应的小鼠模型中，基因治疗或化学诱导剂增强HIF-1活性分别与维持组织灌注有关，从而预防了肢体截肢和同种异体移植排斥反应。因此，在这些临床情况以及其他组织灌注受损在疾病发病机制中起作用的情况下，靶向HIF-1可能具有治疗益处。
