1. Targeting mitochondria-associated membranes as a potential therapy against endothelial injury induced by hypoxia
- Author
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Chen Jian, Yuqi Gao, Chen Dewei, Zhang Erlong, Yi‐Dong Yang, Man-Man Li, Xu Gang, and Sun Binda
- Subjects
0301 basic medicine ,Small interfering RNA ,Vascular smooth muscle ,Nitric Oxide Synthase Type III ,Mitochondrion ,Pulmonary Artery ,Nitric Oxide ,Biochemistry ,Umbilical vein ,03 medical and health sciences ,0302 clinical medicine ,Adenosine Triphosphate ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Molecular Biology ,Inflammation ,Cell growth ,business.industry ,Cell Biology ,Transfection ,Hypoxia (medical) ,Cell Hypoxia ,Cell biology ,Mitochondria ,030104 developmental biology ,Apoptosis ,030220 oncology & carcinogenesis ,Mitochondrial Membranes ,Calcium ,medicine.symptom ,business - Abstract
Mitochondrial dysfunction plays a principal role in hypoxia-induced endothelial injury, which is involved in hypoxic pulmonary hypertension and ischemic cardiovascular diseases. Recent studies have identified mitochondria-associated membranes (MAMs) that modulate mitochondrial function under a variety of pathophysiological conditions such as high-fat diet-mediated insulin resistance, hypoxia reoxygenation-induced myocardial death, and hypoxia-evoked vascular smooth muscle cell proliferation. However, the role of MAMs in hypoxia-induced endothelial injury remains unclear. To explore this further, human umbilical vein endothelial cells and human pulmonary artery endothelial cells were exposed to hypoxia (1% O2 ) for 24 hours. An increase in MAM formation was uncovered by immunoblotting and immunofluorescence. Then, we performed small interfering RNA transfection targeted to MAM constitutive proteins and explored the biological effects. Knockdown of MAM constitutive proteins attenuated hypoxia-induced elevation of mitochondrial Ca2+ and repressed mitochondrial impairment, leading to an increase in mitochondrial membrane potential and ATP production and a decline in reactive oxygen species. Then, we found that MAM disruption mitigated cell apoptosis and promoted cell survival. Next, other protective effects, such as those pertaining to the repression of inflammatory response and the promotion of NO synthesis, were investigated. With the disruption of MAMs under hypoxia, inflammatory molecule expression was repressed, and the eNOS-NO pathway was enhanced. This study demonstrates that the disruption of MAMs might be of therapeutic value for treating endothelial injury under hypoxia, suggesting a novel strategy for preventing hypoxic pulmonary hypertension and ischemic injuries.
- Published
- 2019