Age-related
macular degeneration (AMD), which is characterized by choroidal
neovascularization (CNV), or blood vessel growth, is the primary cause of
blindness in elderly individuals of industrialized countries. The prevalence of
the disease is projected to increase 50% by the year 2020. There is an urgent
need for new pharmacological interventions for the treatment and prevention of
AMD.
Researchers
from Massachusetts Eye and Ear/Schepens Eye Research Institute, Harvard Medical
School and other institutions have demonstrated for the first time that the
omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs), DHA and EPA, and
their specific bioactive products derived from the cytochrome P450 (CYP)
pathway, can influence choroidal neovascularization (CNV) and vascular leakage
by modulating micro-environmental immune cell recruitment to the site of these
lesions. Their findings were
"These
are the first results showing that omega (ω)-3 LCPUFAs and their CYP derived
metabolites can regulate choroidal angiogenesis in vivo. The fact that this can
be accomplished with physiologically relevant naturally occurring lipid
metabolites is of significant clinical interest as these molecules are readily
available and considered to be safe. Our findings not only show promising
therapeutic potential for resolution of neovascular AMD, but also for other
conditions or diseases that involve pathologic angiogenesis and inflammation,”
said Kip Connor, Ph.D., Assistant Professor in Ophthalmology at Harvard Medical
School and senior author of the paper.
The
omega (ω)-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFAs) are two
classes of dietary lipids that are essential fatty acids and have opposing
physiological effects. To evaluate the effect of LCPUFAs on CNV development,
researchers fed mice one of three experimental diets beginning two weeks before
CNV induction by laser photocoagulation. The experimental diets were enriched
with either ω-3 or ω-6 LCPUFAs, or in the case of the control diet, devoid of
the primary ω-3 or ω-6 LCPUFAs. The lesion size and vascular leakage were
significantly smaller in animals fed with ω-3 LCPUFAs. To gain mechanistic
insight into the effect of dietary ω-3 LCPUFAs on CNV regression, researchers
analyzed the lipid profiles of these mice and identified endogenous
CYP-generated metabolites. Specifically, 17,18-EEQ and 19,20-EDP, derived from
the CYP-pathway were identified by liquid chromatography- mass spectrometry
(LC–MS/MS) and found to confer protection. Systemic immune-cell recruitment and
adhesion-molecule regulation were significantly dampened in mice receiving
ω-3s, thereby suppressing inflammation that is thought to exacerbate this
disease. These findings provide a unique mechanism whereby specific CYP derived
lipid metabolites regulate angiogenesis in a mouse model of AMD.
The
researchers demonstrated that dietary supplementation of omega (ω)-3 long-chain
polyunsaturated fatty acids (LCPUFAs) mediates choroidal neovessel regression
in a well-characterized murine model of neovascular AMD. The cytochrome P450
(CYP) enzymes catalyze the epoxidation of these ω-3 LCPUFAs to form the
eicosanoids 17,18-epoxyeicosatetraenoic acid (EEQ) and
19,20-epoxydocosapentaenoic acid (EDP), which were identified as key lipid
mediators of disease resolution.
Their
findings show promising therapeutic potential in AMD disease resolution.
"Given the prevalence of neovascular eye disease, the potential
impact of this study is highly significant. We have identified unique
endogenous lipid biometabolites that are able to inhibit pathologic retinal
angiogenesis, a major driver of vision loss worldwide. It is our hope that
future studies will allow us to develop specific therapeutics that harness this
knowledge resulting in a greater visual outcome and quality of life for
patients suffering from these sight-threatening diseases," said lead
author Ryoji Yanai, M.D., Ph.D.
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