Pulmonary hypertension in humans can result from exposure to low oxygen levels. The disease is characterized by proliferation of smooth muscle cells, endothelial cells, and fibroblasts. These human cells cease to grow after a finite number of population doublings, a process termed replicative senescence. However, hypoxia can increase replicative life span of human fibroblasts and human vascular smooth muscle cells. Our preliminary results confirm these previous observations by demonstrating that hypoxia increases replicative life span in primary human lung fibroblasts. The mechanisms underlying the hypoxic increase in replicative life span of human cells are not fully understood. Current models indicate that cells cultured under hypoxia are likely to endure less oxidative stress compared to cells cultured under normoxia. The decrease in oxidative stress limits DNA damage and telomeric shortening under hypoxia. However, we have shown in numerous studies that hypoxia paradoxically increases oxidative stress. The source of the increase in oxidants is complex III within the mitochondrial electron transport chain. The increase in oxidative stress activates the transcription factor hypoxia inducible factor 1 (HIF-1) during hypoxia. HIF-1 activates a multitude of genes under hypoxia including the human telomerase reverse transcriptase (hTERT) gene, a catalytic subunit of telomerase. Furthermore hypoxia induces phosphorylation of the TERT protein and sustains high levels of TERT protein expression in human aortic vascular smooth muscle cells compared to normoxia. We propose that it is the gain of HIF-1 function during hypoxia and not lowered oxidative stress that allows for the increase in lifespan of lung cells. In this proposal we will test the hypothesis that hypoxia increases mitochondrial generated oxidants to activate HIF-1 and its target gene TERT which are required for the increase in replicative lifespan of human lung fibroblasts and human pulmonary artery smooth muscle cells. Collectively these studies will provide new information regarding mechanisms underlying replicative senescence and the aging process. ? ? ?
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| Bell, Eric L; Klimova, Tatyana A; Eisenbart, James et al. (2007) Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia. Mol Cell Biol 27:5737-45 |
