15.5Oxidized LDL, 7-Ketocholesterol and Age-Related Macular Degeneration

At this time there is no mechanistic evidence to directly link AMD to LDL oxidation and atherosclerosis [4]. However, these two diseases do seem to have some broad mechanisms in common: aging, lipid deposition/oxidation [3, 4, 54], and chronic inflammation [4, 15, 55]. This subject has been recently reviewed elsewhere [3, 4, 54–56] and it is only summarized here.

There is considerable indirect evidence to suggest there may be a connection betweenlipiddeposition/oxidationand agingdiseasessuchasAMD. Epidemiological studies have suggested a link between atherosclerosis and AMD [56, 57]. While these studies may not be conclusive, there is additional support from genetic studies. The genetics of AMD are complex and have been reviewed recently [58, 59]. The AMD-associated genes seem to vary tremendously but do provide some insight into the pathogenesis of this disease and do point to a potential lipid involvement. Most of the associated genes seem to fall into three very broad categories: metabolic/oxidative stress-, immune system-, and lipid-related [58, 59]. These categories are not contradictory since oxidized lipids are proinflammatory and can cause considerable stress and cytotoxicity if not removed and/or metabolized [4]. Some lipid related genes such as apoE, ABCA1, and CETP [60] are of particular interest since they are known to play important roles in the systemic “reverse cholesterol” pathway. This pathway has been identified in the retina [27], but its precise function has not been fully elucidated. Other lipid-related proteins such as the oxysterol binding protein-2 [61] and hepatic lipase [62] are also very interesting. OSBP-2 is known to be expressed in the retina and binds 7KCh [63]. The potential role of lipids and lipid-related genes has been reviewed elsewhere [64, 65].

15.6Treatments for AMD

Present and future treatments for AMD have been recently reviewed [66, 67] and a comprehensive discussion of this literature is beyond the scope of this chapter. Thus, this chapter focuses on the potential treatments for AMD in relation to inflammatory effects caused by lipid oxidation.

As mentioned above, there are two broad categories for AMDs: “wet” or exudative and “dry” or atrophic [1, 58]. During the early stages of the disease these two forms of AMD are essentially indistinguishable. It is only at the late stages when differences emerge [1, 2]. The “wet” form is characterized by the formation of choroidal neovessels that grow through BrM into the macular region. These neovessels can form rapidly and are fragile, which can lead to massive photoreceptor loss if they leak. This form of AMD is responsible for 90% of the cases that lead to legal blindness [1, 2]. The “dry” form, which in its late stages is referred to as geographic atrophy, progresses far more slowly and is generally less severe. The photoreceptor

loss seen in this form of AMD seems to be the result of RPE malfunction likely due to chronic inflammation [66]. There is no effective treatment for “dry” AMD but “wet” AMD can be reasonably successfully treated, at least for a period of time, if caught early before the neovessels leak [67].

The most effective treatment for “wet” AMD is anti-VEGF therapy [66, 67]. These are two forms of anti-VEGF antibodies made by Genentech termed Avastin and Lucentis [67]. Both antibodies are very effective at regressing choroidal neovascularization (CNV) and have revolutionized the field, making laser photocoagulation and photodynamic therapy almost obsolete [67]. The problem with anti-VEGF therapy is that it must be delivered monthly via intraocular injections and that the long-term effects of this therapy are unknown.

OxLDL and 7KCh are very potent inducers of VEGF [15, 26] and considering their presence in choroidal vessels and BrM [26], this may be a source of chronic induction that under the proper conditions results in CNV [4]. If the assumption that oxLDL and 7KCh-mediated inflammation results in CNV formation is correct, then there are several potential treatments available to prevent VEGF release. As mentioned above, certain types of PUFAs such as DHA can ameliorate the 7KChmediated inflammatory responses and VEGF induction (Fig. 15.4, unpublished data). Anti-VEGF therapy may be followed with dietary and/or direct (eye drop) delivery of these effective PUFAs to sustain the VEGF suppression and thus reduce the frequency of the anti-VEGF injections.

Another proposed treatment for AMD has been statins, which are HMG-CoA reductase inhibitors that seem to provide some benefit for coronary heart disease [68]. HMG-CoA reductase is the rate limiting enzyme in the mevalonate pathway that leads to cholesterol synthesis [68]. The majority of cholesterol synthesis occurs in the liver, so these drugs are reasonably effective at lowering total cholesterol levels in the blood by inhibiting hepatic cholesterol synthesis [68]. Despite some potentially serious side effects, statins are considered generally safe and effective for decreasing the incidence of cardiovascular disease [69, 70]. However, their benefits regarding AMD are less clear and more controversial. A comprehensive review of the published literature regarding this issue has been recently published [71]. In essence, more large prospective studies are needed to properly evaluate the benefits of statins in AMD.

The reasons statins are not unequivocally beneficial in the treatment of AMD is likely due to the way the two diseases initiate. The RPE expresses LDL receptors on its basal surface that serve to bind LDL particles [24, 25]. Lowering cholesterol levels to “normal” would not stop the RPE from attracting LDL particles with its receptors. Lipoprotein deposits in BrM and CH are likely forming gradually and perhaps becoming more permanent once oxidized. In the cardiovascular system, deposits also form gradually, but massive depositions that lead to coronary insufficiency and infarcts are suspected of being due to deposit buildup in areas where damage has occurred and platelets have deposited [16, 17]. Statins may be able to prevent the formation of such massive deposits and perhaps even reduce those that have already formed. However, statins are unlikely to aid in the removal of microdeposits in BrM or prevent their oxidation. Nevertheless, statins may prove beneficial

for AMD provided they are used before any significant deposition and oxidation of lipoprotein occurs in BrM. In other words, long-term use of statins may eventually prove beneficial in AMD, although it carries other risks [69–71].

15.7Conclusions

Lipoprotein deposition and oxidation seem to be involved in the pathogenesis of AMD. Accumulation of oxidized lipids in RPE, BrM, and CH in the aging retina impedes the proper flow of nutrients and metabolites. It is also a likely cause of chronic inflammation. These oxidized lipids affect inflammatory signaling receptors in cells causing chronic activation of NFkB mediated pathways which subsequently lead to cellular stress and loss of function. The precise mechanism of this inflammatory process is not well understood, but recent developments suggest that the formation of 7KFAEs may be key activators. This could lead to potential new forms of pharmacological treatments, since certain types of PUFAs seem to inhibit their formation. These findings may also have a broader impact on other aging diseases that may also be mechanistically related to AMD.

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Chapter 16

Hepatocyte Growth Factor Protection

of Retinal Pigment Epithelial Cells

Dan-Ning Hu, Joan E. Roberts, Richard Rosen, and Steven A. McCormick

Abstract Hepatocyte growth factor (HGF) is a pleiotropic growth factor that is mainly expressed in mesenchymal cells. MET (mesenchymal–epithelial transition factor) is a membrane receptor that binds HGF. The receptors for HGF (MET) are primarily found in epithelial cells and several stromal cells. Activation of MET by HGF promotes migration, mitosis, and survival of various cells. HGF protects various cells from oxidative stress-induced apoptosis mainly via the phosphorylation of phosphoinositide 3-kinase/Akt pathway. HGF also plays a role in embryogenesis, tissue repair, and angiogenesis. HGF levels in the ocular fluids are elevated in various ocular diseases related to cell proliferation and angiogenesis. HGF protects retinal pigment epithelial (RPE) cells from hydrogen peroxide-induced apoptosis by inhibition of the mitochondrial apoptotic pathway. In ceramideand glutathione depletion-induced apoptosis of RPE cells, studies have also demonstrated that HGF can protect RPE cells in these oxidative stress models. These studies suggest that HGF is a natural protective factor for RPE cells and plays an autocrine role protecting RPE cells against oxidative stress.

D.-N. Hu (*)

Tissue Culture Center, The New York Eye and Ear Infirmary, 310 East 14th Street, New York, NY 10003, USA

Department of Ophthalmology, New York Medical College, New York, NY, USA e-mail: hu2095@yahoo.com; dhu@nyee.edu

J.E. Roberts

Department of Chemistry, Division of Natural Sciences, Fordham University, New York, NY, USA

R. Rosen

Department of Ophthalmology, Ophthalmology Research, New York Eye and Ear Infirmary, New York Medical College, New York, NY, USA

S.A. McCormick

Department of Pathology and Laboratory Medicine, The New York Eye and Ear Infirmary, New York, NY, USA

Departments of Pathology, Ophthalmology and Otolaryngology, New York Medical College, New York, NY, USA

in Applied Basic Research and Clinical Practice, DOI 10.1007/978-1-61779-606-7_16, © Springer Science+Business Media, LLC 2012