| First Author | Shui YB | Year | 2008 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 49 |
| Issue | 11 | Pages | 4961-70 |
| PubMed ID | 18586877 | Mgi Jnum | J:141905 |
| Mgi Id | MGI:3820011 | Doi | 10.1167/iovs.08-2118 |
| Citation | Shui YB, et al. (2008) HIF-1: an age-dependent regulator of lens cell proliferation. Invest Ophthalmol Vis Sci 49(11):4961-70 |
| abstractText | PURPOSE: The lens grows throughout life, and lens size is a major risk factor for nuclear and cortical cataracts. A previous study showed that the hypoxic environment around the lens suppressed lens growth in older rats. The present study was conducted to investigate the mechanism responsible for the age-dependent decline in lens cell proliferation. METHODS: Transgenic mice expressing Cre recombinase in the lens were bred to mice containing floxed Hif1a alleles. Transgenic mice expressing oxygen insensitive forms of HIF-1alpha in lens epithelial cells were exposed to room air or 60% oxygen. Proliferation was measured by BrdU labeling and cell death by using the TUNEL assay. Morphology was assessed in histologic sections. HIF-1alpha and p27(KIP1) levels were determined by Western blot. The expression of HIF-regulated genes was assessed on microarrays. RESULTS: Lenses lacking Hif1a degenerated, precluding study in older animals. Breathing 60% oxygen reduced HIF-1alpha levels and HIF-1-regulated transcripts in lens epithelial cells from young and older lenses. Overexpression of oxygen-insensitive HIF-1alpha had no effect on lens size, but suppressed increased proliferation in response to oxygen. Systemic injection of the iron chelator, 1,10-phenanthroline prevented the degradation of HIF-1alpha and reduced oxygen-induced proliferation. Increasing oxygen decreased levels of p27(KIP1) in the epithelial cells of older mice, which was prevented by expressing oxygen-insensitive forms of HIF-1alpha. CONCLUSIONS: HIF-1alpha is present and HIF-1 is transcriptionally active throughout life, but suppresses growth only in older lenses. Maintaining elevated levels of p27(KIP1) in older lenses requires HIF-1. p27(KIP1) and other growth regulators may selectively suppress the proliferation of older lens epithelial cells. |
