The retina exhibits an inherent autofluorescence that is imaged ophthalmoscopically as fundus autofluorescence. In clinical settings, fundus autofluorescence examination aids in the diagnosis and follow-up of many retinal disorders. Fundus autofluorescence originates from the complex mixture of bisretinoid fluorophores that are amassed by retinal pigment epithelial (RPE) cells as lipofuscin. Unlike the lipofuscin found in other cell-types, this material does not form as a result of oxidative stress. Rather, the formation is attributable to non-enzymatic reactions of vitamin A aldehyde in photoreceptor cells; transfer to RPE occurs upon phagocytosis of photoreceptor outer segments. These fluorescent pigments accumulate even in healthy photoreceptor cells and are generated as a consequence of the light capturing function of the cells. Nevertheless, the formation of this material is accelerated in some retinal disorders including recessive Stargardt disease and ELOVL-4-related retinal degeneration. As such, these bisretinoid side-products are implicated in the disease processes that threaten vision. In this article, we review our current understanding of the composition of RPE lipofuscin, the structural characteristics of the various bisretinoids, their related spectroscopic features and the biosynthetic pathways by which they form. We will revisit factors known to influence the extent of the accumulation and therapeutic strategies being used to limit bisretinoid formation. Given their origin from vitamin A aldehyde, an isomer of the visual pigment chromophore, it is not surprising that the bisretinoids of retina are light sensitive molecules. Accordingly, we will discuss recent findings that implicate the photodegradation of bisretinoid in the etiology of age-related macular degeneration.

Background-Several studies have shown that both early and late effects of ischemic preconditioning (IPC) protect against myocardial injury after ischemic reperfusion. Methods and Results-The purpose of this study was to evaluate the late effects of IPC on endothelial function in humans.Late phase of IPC was induced by upper limb ischemia (cuff inflation of over 200 mm Hg for 5 minutes) 6 times a day for 1 month. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh) and to sodium nitroprusside (SNP) before and after IPC stimulus in 30 young healthy men. FBF was measured using a strain-gauge plethysmograph. The IPC stimulus significantly increased plasma concentration of vascular endothelial growth factor (VEGF), circulating level of endothelial progenitor cells (EPCs), and FBF responses to ACh, but these did not change in the control group. The FBF responses to SNP were similar before and after the IPC stimulus. Infusion of N G -monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely eliminated the IPC stimulus-induced augmentation of FBF responses to ACh. In the cotralateral arms of subjects that received the IPC stimulus, FBF responses to ACh did not change, but levels of VEGF and circulating EPCs increased. Conclusions-These findings suggest that repetition of late IPC stimulus augments endothelium-dependent vasodilation in humans through increases in nitric oxide production and number of EPCs under a local condition. Repetition of IPC stimulus may be a simple, safe, and feasible therapeutic technique for endothelial protection of peripheral vessels.

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration