Modified Lipoproteins in Diabetic Retinopathy: A Local Action in
Journal of Clinical and Experimental Ophthalmology

Journal of Clinical and Experimental Ophthalmology
Open Access

ISSN: 2155-9570

+44 1223 790975

Review Article - (2013) Volume 4, Issue 6

Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina

Jeremy Y Yu1 and Timothy J Lyons1,2*
1Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Northern Ireland, UK
2Harold Hamm Diabetes Center and Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
*Corresponding Author: Timothy J Lyons, Centre for Experimental Medicine School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Institute For Clinical Science Block A, Grosvenor Road, Belfast BT12 6BA, Northern Ireland, UK, Tel: (+44)-9063-2727 Email:


Clinical epidemiological studies have revealed relatively weak, yet statistically significant, associations between dyslipidemia/dyslipoproteinemia and diabetic retinopathy (DR). Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids. To unify the apparent discrepancies, we hypothesize that plasma lipoproteins play an indirect but important role in DR, contingent on the integrity of the blood-retina-barrier (BRB). In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells. In this hypothesis, BRB leakage is the key, plasma lipoprotein concentrations mainly modulate its consequences, and fenofibrate has intra-retinal actions. This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

Keywords: Blood retina barrier, Diabetic retinopathy, Dyslipidemia, Fenofibrate, Lipoprotein, Oxidized LDL, Pericytes


ACCORD: Action to Control Cardiovascular Risk in Diabetes; Apo: Apolipoprotein; ATF6: Activating Transcription Factor 6; BAX: B-cell Lymphoma 2-Associated X Protein; BCL-2: B-Cell Lymphoma 2; BRB: Blood Retina Barrier; CHOP: C/EBPHomologous Protein; cPLA2: Cytosolic Phospholipase A2; DCCT: Diabetes Control and Complications Trial; EDIC: Epidemiology of Diabetes Interventions and Complications; DME: Diabetic Macular Edema; DR: Diabetic Retinopathy; ER: Endoplasmic Reticulum; ERK: Extracellular Signal-Regulated Kinase; ETDRS: Early Treatment Diabetic Retinopathy Study; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes; GRP78: 78 kDa Glucose-Regulated Protein; HDL: High-Density Lipoprotein; 4-HNE: 4-Hydroxynonenal; HOG-LDL: Highly Oxidized, Glycated LDL; JNK: Jun N-terminal Kinase; LDL: Low-Density Lipoprotein; L-NAME: L-N(G)-nitroarginine Methyl Ester; LOX-1: Lectin-like ox-LDL Receptor 1; MAPK: Mitogen-Activated Protein Kinase; MCP-1: Monocyte Chemoattractant Protein-1; MMP: Matrix Metalloproteinase; NF-κB: Nuclear Factor-κB; N-LDL: Native LDL; NMR-LSP: Nuclear Magnetic Resonance Lipoprotein Subclass Profile; NPDR: Non-proliferative Diabetic Retinopathy; Ox-LDL: Oxidized LDL; PARP: Cleaved Poly ADP Ribose Polymerase; PEDF: Pigment Epithelium-Derived Factor; PPAR: Peroxisome Proliferator Activated Receptors; p-eIF2α: Phospho-eukaryotic Initiation Factor 2α; RPE: Retinal Pigment Epithelium; sXBP1: Spliced X-box Binding Protein 1; TIMP-3: Tissue Inhibitor of Metalloproteinase-3; TUNEL: Terminal Deoxynucleotidyl Transferase dUTP Nick End Labelling; VEGF: Vascular Endothelial Growth Factor

Clinical, Epidemiological Evidence Supports an Indirect, yet Important, Role for Dyslipidemia in DR

The role of dyslipidemia/dyslipoproteinemia in diabetic retinopathy (DR) has been a matter of debate, but the weak associations between plasma lipid levels and DR status have dampened interest. Many earlier studies explored the relationship between circulating levels of lipids and lipoproteins and the severity of DR, either cross-sectionally or longitudinally [1-17]. In general, these revealed correlations between retinopathy and standard measures of plasma cholesterol, including total and LDL cholesterol, and LDL-to-HDL cholesterol ratio. This work has been previously reviewed in detail [18-22], and some recent important studies are summarized below.

The Pittsburgh Epidemiology of Diabetes Complications study [23], a prospective study with 657 type 1 diabetic patients, showed that concentrations of serum triglycerides, and to a lesser extent LDL cholesterol, were associated with retinopathy. Higher levels of LDL cholesterol and triglycerides were associated with progression to proliferative diabetic retinopathy (PDR). In the Early Treatment Diabetic Retinopathy Study (ETDRS), serum lipid levels were measured in 2709 patients [24]: those with elevated total or LDL cholesterol levels at baseline were twice as likely to have retinal hard exudates as those with normal levels. The Hoorn study [25], a population-based cross-sectional study with 2484 diabetic and non-diabetic individuals, found that the prevalence of DR was positively associated with serum cholesterol and triglyceride levels, and that retinal hard exudates were associated with elevated total and LDL cholesterol. In the Atherosclerosis Risk In Communities study [26], the presence of retinal hard exudates was correlated with LDL cholesterol and lipoprotein (a). With the aid of improved lipoprotein fractionation technology, we evaluated the relationship of plasma lipoproteins with DR in more detail in a Diabetes Control and Complications Trial (DCCT) sub-cohort of 988 type 1 diabetic patients (440 women and 548 men) [27]. Lipoproteins were measured by conventional lipid profile and nuclear magnetic resonance lipoprotein subclass profile (NMR-LSP), and in addition, apolipoprotein A1 (apoA1), apoB, lipoprotein (a), and susceptibility of LDL to oxidation were determined. Conventional profiles showed that the severity of retinopathy was positively associated with triglycerides and negatively with HDL cholesterol. NMR-LSP measures identified retinopathy as being associated with small and medium VLDL and negatively with VLDL size. In male subjects only, retinopathy was positively associated with small LDL, LDL particle concentration, apoB concentration, and small HDL, and negatively associated with large LDL, LDL size, large HDL, and HDL size. The findings were consistent with a role for dyslipoproteinemia in the pathogenesis of DR. Most recently, in a cross-sectional study of 224 type 1 and type 2 diabetic patients, apoA1 (inverse association), apoB and apoB-to-apoA1 ratio (positive associations) were significantly and independently associated with DR and its severity [28]. Serum apolipoprotein levels were believed to be stronger biomarkers for DR than the traditional lipid measures in that study [28].

Overall, a prominent conclusion of most of the epidemiological studies is the positive association between plasma LDL (i.e. levels of apoB and cholesterol, or particle size) and DR. However, this association, although of statistical significance, is only moderate in magnitude, and not of sufficient strength to be useful in defining a patient’s individual risk for DR. A further consideration is that, without diabetes, dyslipidemia does not appear to cause retinal disease, and native LDL even at higher concentrations does not pose significant toxicity to cultured retinal cells.

Besides quantitative lipid measures, qualitative changes of lipoproteins such as formation of oxidized LDL (ox-LDL; for a detailed review refer to [29]), a well-established risk factor for atherosclerosis [30-32], have also been associated with retinopathy. A small but significant amount of ox-LDL (ranging from 0.001% in healthy people to 5% of total LDL in disease states [33]) was detectable in plasma, and was elevated significantly in diabetes [29]. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, we showed that increased circulating levels of AGE-LDL- and ox-LDL-immune complexes were associated with higher risk of severe non-proliferative retinopathy (NPDR) and PDR in type 1 diabetes over many years [34]. In this cohort, ox-LDL-immune complexes were also associated with the progression of carotid intima-media thickness [35] and coronary calcification [36]. In type 2 diabetes, it has been reported that patients affected by retinopathy had higher levels of IgG autoantibodies against malondialdehyde-modified apoB-100 in their circulation [37], and the authors also found that higher levels of IgG specific for the native apoB- 100 fragments p45 and p210 were associated with DR, but appeared to be protective of coronary disease progression [37]. The reason for such an apparent difference between micro- and macro-vascular complications is unclear and needs to be further elucidated. Overall, the data support a role for modified lipoproteins in the pathogenesis of DR.

Interest in the role of lipids and lipoproteins has been amplified recently by the results of two large prospective studies of type 2 diabetes patients, Action to Control Cardiovascular Risk in Diabetes (ACCORD) [38] and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study [39], which demonstrated unexpected yet robust benefits of fenofibrate, a drug that has been used to reduce elevated plasma triglycerides, on DR. In the ACCORD study, after 4 years, fenofibrate reduced the rate of DR progression (6.5% vs. 10.2% with placebo) by at least three steps on the ETDRS Severity Scale in patients who were also receiving simvastatin. In the FIELD study, fenofibrate reduced the frequency of laser treatment for diabetic macular edema (DME) by 31% and for PDR by 30%. Interestingly, however, its effect was not clearly attributable to the systemic lipid-lowering effects[39], suggesting that the mechanisms could be unrelated to the drug’s effects on plasma lipids, and/or could be related to tissue lipid processing that is not readily reflected in systemic circulation: i.e. fenofibrate may act through intra-retinal pleiotropic effects. In this regard, fenofibrate has been reported to decrease plasma ox-LDL [40], modulate the lectinlike ox-LDL receptor 1 (LOX-1, scavenger receptor for ox-LDL) [41], and attenuate cellular effects of ox-LDL [42]. We have shown that, in diabetic animal models, intravitreal fenofibrate attenuated angiogenic and inflammatory responses via the PPARα receptor [43]. In addition, mechanisms independent of PPARα receptor have been reported for fenofibrate [44,45], and may contribute to the attenuation of lipotoxicity in retinal pericytes [46]. The findings with fenofibrate were not entirely without precedent: many years ago, another fibrate drug, clofibrate [47], and more recently etofibrate [48], were also shown to have beneficial effects on DR. Of interest, ‘statins’ which are generally more effective than fibrates in preventing cardiovascular events, seem to be less beneficial than fibrates in DR: they have, however, been shown to reduce retinal hard exudates [49].

A Unifying Hypothesis for Lipoproteins in DR

To provide a working model that will connect the apparently disparate observations (i.e. relatively weak association data from epidemiological studies, robust efficacy of fenofibrate in clinical intervention studies, and extensive laboratory data showing deleterious effects of modified, but not native, lipoproteins on retinal cells (discussed below)), our evolved thinking is that plasma lipoproteins play a ‘hidden’, indirect role on DR, which is dependent on the breakdown of the blood-retina-barrier (BRB) (Figure 1). In normal retina with an intact BRB, plasma lipoproteins are largely irrelevant; however, their effects become operative after the BRB becomes deficient (as in diabetes), allowing extravasation of lipoproteins which then become modified (i.e. oxidized and/or glycated) in tissue, rendering them toxic towards nearby retinal cells. In this hypothesis, BRB leakage is the key, and plasma lipoprotein concentrations simply modulate its consequences. One limitation of the model is that the action of lipoproteins occurs only as a secondary effect of BRB leakage, not as the primary initiator. BRB impairment may be caused by many common, intermittent metabolic stresses that are present in diabetes, such as high and fluctuating glucose, free fatty acids, oxidative stress and osmotic stress [50-54], all of which may be acutely exacerbated during episodes of ketoacidosis. Extravasation of lipoproteins, we suggest, can gradually turn a transitory BRB impairment into prolonged, chronic pathology. Also, because of their cytotoxic effects on retinal capillary cells, higher levels of ox-LDL in circulation may pose a direct noxious effect on the BRB [55-57], contributing to the initiation of damage. Overall, the role of ox-LDL in DR is essentially analogous to that in atherosclerosis, in which elevated plasma levels of LDL and modified LDL are associated with cardiovascular disease, where the modification of LDL and its harmful effects occur primarily in the arterial intima, not in plasma. In the retina, certain unique features are operative: retinal lipoprotein exudates appear in the perivascular extracellular space adjacent to the neural retina, due to the small size of retinal capillaries [49], and may thus produce generalized retinal neurovascular injuries [58]. Also, because LDL is normally excluded completely from the retina, the ‘fold increase’ once BRB leakage occurs is much greater in the retina than in the arterial intima.


Figure 1: A working hypothesis of modified lipoproteins in the pathogenesis of DR. The role of circulating lipoproteins in DR depends on the integrity of BRB. Normally, plasma LDL does not cause retinal damage, but plasma ox- LDL (mostly mildly modified) may contribute to the initial BRB impairment, together with many other metabolic factors that are commonly seen in diabetes. Once the BRB becomes leaky, even in a short period, LDL can extravasate, aggregate, and become progressively modified by oxidation and glycation in the extracellular milieu, resulting in generalized damages to all retinal cell types in proximity. Extravasation of lipoproteins is expected to gradually turn intermittent, transient BRB impairment into a prolonged, chronic pathological state. In this model, fenofibrate may attenuate retinopathy by modulating intraretinal lipid processing and inflammation, with the efficacy unrelated to its systemic lipid-lowering effect. The retinal pathology caused by extravascular modified lipoproteins is largely isolated from the circulating lipids, consistent with the generally weak association between plasma lipids and DR in epidemiological studies.

Consistent with this model for DR, Benarous et al. [59] recently proposed that serum lipids were involved in the late-stage, severe form of DME, through lipoprotein exudation following BRB breakdown. In a prospective cohort of 500 type 1 and type 2 diabetic patients, they reported that serum lipids were independently associated with the clinically significant macular edema only, but not with DR, or with mild or moderate DME. Indeed, since DME occurs after BRB breakdown, dyslipidemia may be more of a risk factor for DME than for DR [60]. We suggest that LDL extravasation occurs not only in late-stage DME, but also in DR, even at very early stage of the disease. Supporting this, in human diabetic retina, we showed that extravascular apoB and ox- LDL were detectable prior to clinical retinopathy (discussed below), suggesting that lipoproteins mediate early pathogenesis of the disease.

Presence of Modified Lipoproteins in Diabetic Retina of Humans and Animals

To provide evidence that ox-LDL is indeed present in the extracellular space in retinas of DR patients, we recently conducted immunohistochemistry of apoB-100, ox-LDL (antibody against copper-oxidized LDL) and macrophages on the post-mortem retinas from both non-diabetic and type 2 diabetic individuals with varying degrees of DR [61]. Lipoprotein extravasation was observed in all diabetic patients, with the extent correlating with the severity of retinopathy (i.e. diabetic without clinical DR < non-PDR < PDR), but was entirely absent in non-diabetic controls. The finding of ox-LDL in diabetic retinal tissue prior to the onset of clinical DR is consistent with its role in promotion of early DR. Ox-LDL first appeared in the inner retina (i.e. ganglion cell layer) where most blood flow is from the central retinal artery, and permeated later to the outer retina that receives the choroidal circulation. In addition, macrophage infiltration was prominent in retinal sections from patients with PDR. These changes were also accompanied with Terminal-dUTP-Nick-End- Labeling (TUNEL) positive cells in retinas from the diabetic patients, but absent in those from non-diabetic subjects, suggesting cytotoxicity by modified LDL in promoting DR. The data were in line with an earlier case report showing the presence of extravascular apoB, cholesteryl ester and macrophages in retinas obtained from two patients with diabetic maculopathy [49].

Intra-retinal modified LDL has also been observed in a diabetic animal model. Using Akita mice, a well-established model for DR, we detected marked increase of both oxidized and glycated LDL in retina at 13 weeks of age, as compared with wild-type controls; the immunostaining intensity was attenuated following anti-oxidant treatment [62]. It is notable that the timing of our detection of extravasated modified LDL was probably at the early stage of vascular permeability changes in this mouse model, consistent with our findings in humans. Barber et al., also using Akita mice, found increased retinal vascular permeability after 12 weeks of hyperglycemia (~16 weeks of age), but changes of morphology (reduction in the thickness of inner plexiform and nuclear layers, and reduction in the number of cell bodies in the ganglion cell layer) occurred later, after 22 weeks of hyperglycemia, and acellular capillaries and altered morphology of astrocytes and microglia occurred only after 36 weeks of hyperglycemia [63]. Han et al. reported that the early signs of vascular damage (pericyte ghosts, vascular leakage, and microaneurysm formation) appeared at a later stage, approximately 4 months after hyperglycemia, followed by neovascularization 7 months after hyperglycemia [64].

Effects and Mechanisms of Action of Modified LDL on Retinal Cells

Retinal capillary cells

We have accumulated considerable evidence of injurious effects of modified LDL towards a variety of retinal cell types in vitro. Since capillary damage, and especially pericyte loss, represents one of the earliest pathological features of DR [65,66], extensive efforts have been made to define the effects of modified lipoproteins on retinal vascular cells, although it is recognized that even early DR could involve a broader neurovascular insult [58]. LDL was obtained from healthy donors and modified ex vivo to simulate the various degrees of glycation and/or oxidation that occur in diabetes [67,68]. We first tested mildly modified forms of human LDL on bovine retinal capillary endothelial cells and pericytes [67], with the intent of determining whether mild glycation and/or oxidation of LDL occurring in the circulation [29] might contribute to the initiation of retinal capillary injury. We found reduced survival of both cell types upon exposure to low levels of modified LDL, and that toxicity increased in the following order: normal < glycated ≤ minimally oxidized < glycoxidized LDL [67]. The non-modified, native LDL was ineffective in causing cellular damage, suggesting that higher levels of plasma LDL per se do not cause injury to retinal vasculature unless modified under diabetic conditions.

Realizing that extravasated, sequestered lipoproteins experience more extensive modification [29], by both oxidation and glycation, than that which occurs in plasma, we have employed LDL preparations with higher degrees of modification in recent studies. The “highly oxidized, glycated” LDL (HOG-LDL) was prepared by copper oxidization, which generates epitopes on LDL similar to those found in humans [29,61]. The modified LDL was applied to cells typically at concentrations ranging up to approximately 30% of plasma LDL level, which we considered physiologically conservative since the tissue levels of ox-LDL are actually considerably higher than in plasma. Thus in atherosclerosis, ox-LDL concentration may be as much as 70-fold higher than in plasma [31]; and since plasma has ample antioxidant capacity, it is possible that most circulating ox-LDL may originate via ‘reflux’ from plaques [69]. The measures of intra-mural ox-LDL concentrations typically represent average values, and may therefore be misleading: for a substance that is non-uniformly distributed, local concentrations at points of retinal vascular leakage or in arterial plaque could be much higher. Such localized LDL leakage and aggregation are reflected by the patchy distribution of apoB and ox-LDL staining in human diabetic retina [61].

When exposed to HOG-LDL, cultured human retinal pericytes experienced significant toxicity, via caspase-dependent apoptosis, in a dose- and time-related fashion [61,62,70-73]. HOG-LDL also appeared to induce autophagy in pericytes, which may represent an alternative cell fate under oxidative stress [72,74]. Several mechanisms including oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis have been explored in detail. Oxidative stress has long been considered an initiating factor in diabetic complications and DR [75]. In pericytes, HOG-LDL increased intracellular reactive oxygen species, peroxynitrite (ONOO-), inducible nitric oxide synthase, nitric oxide, as well as 3-nitrotyrosine levels, but depleted the level of glutathione peroxidase 1; these findings are indicative of both oxidative and nitrosative stresses [72,76]. Modification of LDL after α-tocopherol enrichment [77], or in the presence of aminoguanidine [73], abolished the adverse effects of glycated, oxidized, and glycoxidized LDL on bovine retinal endothelial cell and pericyte survival and other endpoints. In the retina from diabetic rats, we detected significantly elevated levels of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine compared with non-diabetic rats [78]. With regard to the nitrosative stress, we have described at least one affected pathway that may contribute to pericyte apoptosis. In both human retinal pericyte culture and the retina of Akita diabetic mice, HOG-LDL induced tyrosine nitration of prostacyclin synthase and decreased its activity, resulting in thromboxane receptor stimulation which subsequently mediated pericyte apoptosis [62]. The apoptosis was attenuated by inhibition of the thromboxane receptor or cyclooxygenase-2, and also by restoration of the prostacyclin synthase activity with superoxide dismutase or L-N(G)-nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) [62]. It has been reported that ox-LDL, but not native LDL, markedly increased lipid peroxidation, cytosolic phospholipase A2 (cPLA2) activation, and arachidonic acid release in a time- and dose-dependent manner in retinal pericytes; these effects were strongly inhibited by cPLA2 inhibition, and by α-tocopherol [79].

Lipid peroxidation, phospholipase A2 activation, and modulation of the downstream eicosanoids represent a classic link between oxidative stress and inflammatory responses. Similar to its effects in pericytes, ox-LDL also activated cPLA2 and released arachidonic acid in both macrophages and fibroblasts; loss of cPLA2 activity, either by genetic knockout in mice, or by treatment with a cPLA2 inhibitor, resulted in attenuation of arachidonic acid release and apoptosis in response to ox- LDL [80]. In parallel findings using rat renal mesangial cells, activation of cPLA2 by ox-LDL resulted in prostaglandin E2 production, which was suppressed by α-tocopherol [81]. In addition, ox-LDL induced cyclooxygenase-2 protein expression and prostaglandin E2 release in endothelial cells [82], consistent with a higher expression of cyclooxygenase-2 in human diabetic retina [83]. Nonsteroidal antiinflammatory drugs including selective cyclooxygenase-2 inhibitors were beneficial in experimental DR [84], and also showed promise in reducing fluorescein leakage in a small pilot clinical study [85], although that study failed to demonstrate significant benefits in visual function in patients with DME. In our earlier gene array studies we observed altered gene expression of prostaglandin E synthase in human retinal pericytes after exposure to HOG-LDL, but the level of prostaglandin E2 was not measured in that study [68]. These data highlight the importance of the eicosanoid pathway in mediation of ox-LDL-induced inflammation in retinal vasculature.

Some other cellular markers of inflammation have been evaluated. HOG-LDL increased the monocyte chemoattractant protein-1 (MCP- 1) secretion, and nuclear factor-κB (NF-κB) activation in human retinal pericytes; the effects were attenuated by pigment epitheliumderived factor (PEDF) in a dose-dependent manner, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockage of NF-κB activation [76]. HOG-LDL also selectively reduced the expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) at both mRNA and protein levels in pericytes, a unique effect amongst all other matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs) [86]. Additional evidence that HOG-LDL induces inflammation in pericytes includes up-regulation of the acutephase gene, pentraxin 3 [68], which was also up-regulated by ox-LDL in human vascular smooth muscle cells [87] and strongly expressed in atherosclerotic lesions [88].

ER stress has been a newly discovered mechanism that is implicated in DR, and can be induced by ox-LDL [72,89-92]. When incubated with HOG-LDL, human retinal pericytes exhibited eIF2α phosphorylation, ATF6 nuclear translocation, and increased GRP78, typical signs of ER stress [72]. HOG-LDL also increased the expression of sXBP-1 (a transcription factor involved in ER stress), CHOP (an ER specific proapoptotic factor), and other pro-apoptotic factors including caspase-3 and BAX, but decreased the anti-apoptotic protein BCL-2. These data suggest that HOG-LDL induces ER stress and CHOP activation in pericytes, resulting in transcription of a series of pro-apoptotic genes and suppression of BCL-2, eventually leading to apoptosis [72]. ER stress markers were elevated in the retina of a mouse model of combined diabetes and hypercholesterolemia, compared with that of either diabetes or hyperlipidemia alone [72], and were also detectable in the retina of diabetic patients, but not in non-diabetic individuals [72].

To explore the additional mechanisms underlying the apoptosis induced by modified LDL, we investigated the mitogen-activated protein kinase (MAPK) pathway [71]. Exposure to HOG- vs. N-LDL induced similar degrees of phosphorylation of extracellular signalregulated kinase (ERK), p38, and Jun N-terminal kinase (JNK), and inhibition of ERK, p38, and JNK phosphorylation did not attenuate apoptosis, suggesting that modified LDL elicits apoptosis independent of the MAPK pathway [71]. Recently, we reported evidence supporting a role of the Wnt signaling pathway in DR [78,93]. In retinas from patients with DR and diabetic animals, we detected elevated levels and nuclear translocation of β-catenin, a key effector in the canonical Wnt pathway, together with higher levels of LDL receptor-related proteins 5 and 6, co-receptors of Wnts. Activation of β-catenin by high glucose was attenuated by aminoguanidine, indicative of a role of oxidative stress in the Wnt pathway activation. Consistent with this, Dickkopf homolog 1, a specific inhibitor of the Wnt pathway, ameliorated retinal inflammation and vascular leakage in streptozotocin-diabetic rats, and neovascularization in an oxygen-induced-retinopathy model [93]. In a more recent study, 4-HNE, an important component of ox-LDL, activated the Wnt pathway in retinal endothelial cells and retinal pigment epithelial (RPE) cells; the effect was blocked by the antioxidant, n-acetylcysteine (NAC) [78]. In streptozotocin-diabetic rats, NAC treatment reduced 4-HNE and 3-nitrotyrosine levels, and attenuated the Wnt pathway activity in retina [78].

To gain a panoramic view of the gene expression in pericytes in response to modified lipoproteins, we conducted a microarray study, in which human retinal perictyes were incubated with HOG-LDL vs. glycated LDL vs. native LDL [68]. HOG-LDL induced a gene expression pattern that was markedly distinct from that of N-LDL or G-LDL, whereas the latter two shared a similar expression pattern. A comparison of the responses to HOG- relative to N-LDL revealed 60 genes with differential expression over 1.7 fold in quadruplicate experiments. The HOG-LDL-responsive genes represented members of multiple functional pathways, including fatty acid, eicosanoid, and cholesterol metabolism, fibrinolytic regulation, cell growth and proliferation, cell stress responses, the kinin system, and angiogenesis. These data will help delineate the signalling pathways responsive to modified LDL in pericytes.

Non-vascular retinal cells

We have recently examined the effects of HOG-LDL on cultured human retinal Müller cells, measuring cell viability, oxidative stress, and ER stress [91]. HOG-LDL reduced cell viability by triggering apoptosis, as shown by increased TUNEL staining, higher levels of cleaved PARP and caspase-3, as well as altering the balance between BAX and BCL-2 in favor of apoptosis. HOG-LDL enhanced both oxidative and ER stresses in Müller cells; and inhibition of either of these stresses attenuated apoptosis. Further, inhibition of oxidative stress by NAC resulted in reduced ER stress, suggesting that the latter is downstream of the former. The effects of HOG-LDL were largely mimicked by 7-ketocholesterol and 4-HNE, two major components of modified LDL.

Recently, we explored the effect of HOG-LDL on human RPE cells [94]. As in other cells, HOG-LDL induced ER stress and reduced the viability in RPEs. Both apoptosis and autophagy contributed to the cell death. We further tested the potential beneficial effects of HDL on HOG-LDL-induced toxicity: native HDL, but not oxidized or glycated HDL, protected RPEs from the insult of HOG-LDL, suggesting that loss of HDL protection due to modification by oxidation and/or glycation in diabetes may represent another mechanism contributing to DR development.

The anatomical positioning of the RPE layer enables the numerous functions of these cells to support the neural retina. These include formation of the outer BRB, supply and exchange of nutrients between retina and choroidal vasculature, retinoid storage and metabolism, maintenance of photoreceptor outer segment length, secretion of growth factors, and many others [95]. Dysfunction of the RPE is recognized in age-related macular degeneration, and has increasingly been implicated in DR [96]. As part of its role in retinal lipid metabolism, the RPE internalizes LDL and ox-LDL in large quantities, via the LDL receptor and CD36 scavenger receptor, respectively [97,98]. Consistent with our findings, earlier studies have shown that ox-LDL impairs processing of outer rod and cone segments by the RPE by perturbing the fusion of lysosomes with phagosomes [99,100], thus accelerating the onset of RPE senescence and death [57,101- 103], increasing VEGF and decreasing PEDF expression [57,102,104], impairing outer BRB integrity [57], and enhancing oxidative stress and inflammation [57]. In RPE cells, β-catenin was also elevated by ox-LDL [57], similar to the effect observed in retinal pericytes [78,93]. Overall, the data indicate that extravasated, modified LDL is injurious to retinal cell types beyond the capillary vascular cells, and thus may contribute to the generalized pathology in DR.


In conclusion, we propose a hypothesis that serves to unify the data from epidemiological studies, recent clinical trials with fenofibrate intervention, and exploratory laboratory work. In this hypothesis, lipoproteins in the circulation have an indirect, yet important, role in the development of DR, which is contingent on BRB impairment and lipoprotein extravasation, patchy at first, but later widespread. Extravasated lipoproteins become modified by oxidation and glycation, subsequently contributing to prolonged, widespread retinal neurovascular injuries. Additional studies are ongoing to characterize the detailed mechanisms of lipoprotein-mediated retinal injuries: it is hoped that these will offer deeper insights into the DR pathogenesis, and will lead to new measures for prevention and therapy.


The authors acknowledge grant funding in support of this work from the National Institutes of Health (R29-10697, PO1-HL55782, R21-HL-80921, P20- RR024215), the American Diabetes Association, the Oklahoma Center for the Advancement of Science and Technology (HR08-067), the Presbyterian Health Foundation of Oklahoma City, the Diabetes Research and Wellness Foundation, and the Linjo Fund.


  1. Dornan TL, Carter RD, Bron AJ, Turner RC, Mann JI (1982) Low density lipoprotein cholesterol: an association with the severity of diabetic retinopathy. Diabetologia 22: 167-170.
  2. KEIDING NR, MANN GV, ROOT HF, LAWRY EY, MARBLE A (1952) Serum lipoproteins and cholesterol levels in normal subjects and in young patients with diabetes in relation to vascular complications. Diabetes 1: 434-440.
  3. LOWY AD Jr, BARACH JH (1957) A study of serum lipoprotein and cholesterol determinations in 901 diabetics. Diabetes 6: 342-353.
  4. Bhan CK, Kumar V, Ahuja MM (1971) [Studies on neutral fat, lipoproteins and lipoprotein lipase in relation to vascular disease in young Indian diabetics]. Acta Diabetol Lat 8: 638-648.
  5. Kissebah AH, Kohner EM, Lewis B, Siddiq YK, Lowy C, et al. (1975) Plasma-lipids and glucose/insulin relationship in non-insulin-requiring diabetics with and without retinopathy. Lancet 1: 1104-1108.
  6. Eckel RH, McLean E, Albers JJ, Cheung MC, Bierman EL (1981) Plasma lipids and microangiopathy in insulin-dependent diabetes mellitus. Diabetes Care 4: 447-453.
  7. Mohan R, Mohan V, Susheela L, Ramachandran A, Viswanathan M (1984) Increased LDL cholesterol in non-insulin-dependent diabetics with maculopathy. Acta Diabetol Lat 21: 85-89.
  8. Chakraborty A, Mondal PR, Kundu SC, Batabyal SK (1986) Serum lipids and lipoproteins in diabetic retinopathy. J Assoc Physicians India 34: 631-632.
  9. Miccoli R, Odello G, Giampietro O, Marchetti P, Cristofani R, et al. (1987) Circulating lipid levels and severity of diabetic retinopathy in type I diabetes mellitus. Ophthalmic Res 19: 52-56.
  10. Kostraba JN, Klein R, Dorman JS, Becker DJ, Drash AL, et al. (1991) The epidemiology of diabetes complications study. IV. Correlates of diabetic background and proliferative retinopathy. Am J Epidemiol 133: 381-391.
  11. Sinav S, Onelge MA, Onelge S, Sinav B (1993) Plasma lipids and lipoproteins in retinopathy of type I (insulin-dependent) diabetic patients. Ann Ophthalmol 25: 64-66.
  12. West KM, Erdreich LJ, Stober JA (1980) A detailed study of risk factors for retinopathy and nephropathy in diabetes. Diabetes 29: 501-508.
  13. Nathan DM, Singer DE, Godine JE, Harrington CH, Perlmuter LC (1986) Retinopathy in older type II diabetics. Association with glucose control. Diabetes 35: 797-801.
  14. Agardh CD, Agardh E, Bauer B, Nilsson-Ehle P (1988) Plasma lipids and plasma lipoproteins in diabetics with and without proliferative retinopathy. Acta Med Scand 223: 165-169.
  15. Dhir SP, Dahiya R, Ram J, Dash RJ, Chakravarti RN (1984) Serum lipoprotein cholesterol profile in diabetic retinopathy. Indian J Ophthalmol 32: 89-91.
  16. Klein BE, Moss SE, Klein R, Surawicz TS (1991) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology 98: 1261-1265.
  17. Mehrotra AN, Agarwal N, Jain BS, Jain PK, Arora RC, et al. (1988) A study of serum lipids in diabetic retinopathy. Mater Med Pol 20: 165-167.
  18. Su DH, Yeo KT (2000) Diabetic retinopathy and serum lipids. Singapore Med J 41: 295-297.
  19. Chew EY (1997) Diabetic retinopathy and lipid abnormalities. Curr Opin Ophthalmol 8: 59-62.
  20. Busik JV, Esselman WJ, Reid GE (2012) Examining the role of lipid mediators in diabetic retinopathy. Clin Lipidol 7: 661-675.
  21. Lim LS, Wong TY (2012) Lipids and diabetic retinopathy. Expert Opin Biol Ther 12: 93-105.
  22. Jenkins AJ, Rowley KG, Lyons TJ, Best JD, Hill MA, et al. (2004) Lipoproteins and diabetic microvascular complications. Curr Pharm Des 10: 3395-3418.
  23. Lloyd CE, Klein R, Maser RE, Kuller LH, Becker DJ, et al. (1995) The progression of retinopathy over 2 years: the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. J Diabetes Complications 9: 140-148.
  24. Chew EY, Klein ML, Ferris FL 3rd, Remaley NA, Murphy RP, et al. (1996) Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol 114: 1079-1084.
  25. van Leiden HA, Dekker JM, Moll AC, Nijpels G, Heine RJ, et al. (2002) Blood pressure, lipids, and obesity are associated with retinopathy: the hoorn study. Diabetes Care 25: 1320-1325.
  26. Klein R, Sharrett AR, Klein BE, Moss SE, Folsom AR, et al. (2002) The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the atherosclerosis risk in communities study. Ophthalmology 109: 1225-1234.
  27. Lyons TJ, Jenkins AJ, Zheng D, Lackland DT, McGee D, et al. (2004) Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 45: 910-918.
  28. Sasongko MB, Wong TY, Nguyen TT, Kawasaki R, Jenkins A, et al. (2011) Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids. Diabetes Care 34: 474-479.
  29. Levitan I, Volkov S, Subbaiah PV (2010) Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal 13: 39-75.
  30. Virella G, Lopes-Virella MF (2012) The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes. Front Endocrinol (Lausanne) 3: 76.
  31. Nishi K, Itabe H, Uno M, Kitazato KT, Horiguchi H, et al. (2002) Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler Thromb Vasc Biol 22: 1649-1654.
  32. Ylä-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, et al. (1989) Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 84: 1086-1095.
  33. Holvoet P, De Keyzer D, Jacobs DR Jr (2008) Oxidized LDL and the metabolic syndrome. Future Lipidol 3: 637-649.
  34. Lopes-Virella MF, Baker NL, Hunt KJ, Lyons TJ, Jenkins AJ, et al. (2012) High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes. Diabetes Care 35: 1333-1340.
  35. Lopes-Virella MF, Hunt KJ, Baker NL, Lachin J, Nathan DM, et al. (2011) Complications Trial/Epidemiology of Diabetes I, Complications Research G: Levels of oxidized LDL and advanced glycation end products-modified LDL in circulating immune complexes are strongly associated with increased levels of carotid intima-media thickness and its progression in type 1 diabetes. Diabetes 60: 582-589.
  36. Lopes-Virella MF, Baker NL, Hunt KJ, Lachin J, Nathan D, et al. (2011) Oxidized LDL immune complexes and coronary artery calcification in type 1 diabetes. Atherosclerosis 214: 462-467.
  37. Fredrikson GN, Anand DV, Hopkins D, Corder R, Alm R, et al. (2009) Associations between autoantibodies against apolipoprotein B-100 peptides and vascular complications in patients with type 2 diabetes. Diabetologia 52: 1426-1433.
  38. ACCORD Study Group, ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, et al. (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363: 233-244.
  39. Keech A, Simes RJ, Barter P, Best J, Scott R, et al. (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366: 1849-1861.
  40. Dong Y, Steffen BT, Cao J, Tsai AK, Ordovas J, et al. (2011) Effects of fenofibrate on plasma oxidized LDL and 8-isoprostane in a sub-cohort of GOLDN participants. Atherosclerosis 214: 422-425.
  41. Hayashida K, Kume N, Minami M, Kataoka H, Morimoto M, et al. (2001) Peroxisome proliferator-activated receptor a ligands increase lectin-like oxidized low density lipoprotein receptor-1 expression in vascular endothelial cells. Ann N Y Acad Sci 947: 370-372.
  42. Liang B, McMaster JC, Kroeger EA, Hatch GM, Mymin D, et al. (2000) The effect of fenofibrate treatment on endothelium-dependent relaxation induced by oxidative modified low density lipoprotein from hyperlipidemic patients. Mol Cell Biochem 207: 123-129.
  43. Chen Y, Hu Y, Lin M, Jenkins AJ, Keech AC, et al. (2013) Therapeutic effects of PPARalpha agonists on diabetic retinopathy in type 1 diabetes models. Diabetes 62: 261-272.
  44. Kim J, Ahn JH, Kim JH, Yu YS, Kim HS, et al. (2007) Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway. Exp Eye Res 84: 886-893.
  45. Cacicedo JM, Yagihashi N, Keaney JF Jr, Ruderman NB, Ido Y (2004) AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun 324: 1204-1209.
  46. Cacicedo JM, Benjachareonwong S, Chou E, Yagihashi N, Ruderman NB, et al. (2011) Activation of AMP-activated protein kinase prevents lipotoxicity in retinal pericytes. Invest Ophthalmol Vis Sci 52: 3630-3639.
  47. Nolan J, Cullen JF (1969) Present status of clofibrate therapy in ophthalmology. Br J Ophthalmol 53: 9-15.
  48. Emmerich KH, Poritis N, Stelmane I, Klindzane M, Erbler H, et al. (2009) [Efficacy and safety of etofibrate in patients with non-proliferative diabetic retinopathy]. Klin Monbl Augenheilkd 226: 561-567.
  49. Cusick M, Chew EY, Chan CC, Kruth HS, Murphy RP, et al. (2003) Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels. Ophthalmology 110: 2126-2133.
  50. Hirsch IB, Brownlee M (2005) Should minimal blood glucose variability become the gold standard of glycemic control? J Diabetes Complications 19: 178-181.
  51. Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107: 1058-1070.
  52. Laties AM, Rapoport S (1976) The blood-ocular barriers under osmotic stress. Studies on the freeze-dried eye. Arch Ophthalmol 94: 1086-1091.
  53. Pannicke T, Iandiev I, Wurm A, Uckermann O, vom Hagen F, et al. (2006) Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. Diabetes 55: 633-639.
  54. Martin SL, Hoffman WH, Marcus DM, Passmore GG, Dalton RR (2005) Retinal vascular integrity following correction of diabetic ketoacidosis in children and adolescents. J Diabetes Complications 19: 233-237.
  55. Schreurs MP, Hubel CA, Bernstein IM, Jeyabalan A, Cipolla MJ (2013) Increased oxidized low-density lipoprotein causes blood-brain barrier disruption in early-onset preeclampsia through LOX-1. FASEB J 27: 1254-1263.
  56. Chang HC, Chen TG, Tai YT, Chen TL, Chiu WT, et al. (2011) Resveratrol attenuates oxidized LDL-evoked Lox-1 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab 31: 842-854.
  57. Kim JH, Lee SJ, Kim KW, Yu YS, Kim JH (2012) Oxidized low density lipoprotein-induced senescence of retinal pigment epithelial cells is followed by outer blood-retinal barrier dysfunction. Int J Biochem Cell Biol 44: 808-814.
  58. Antonetti DA, Klein R, Gardner TW (2012) Diabetic retinopathy. N Engl J Med 366: 1227-1239.
  59. Benarous R, Sasongko MB, Qureshi S, Fenwick E, Dirani M, et al. (2011) Differential association of serum lipids with diabetic retinopathy and diabetic macular edema. Invest Ophthalmol Vis Sci 52: 7464-7469.
  60. Ding J, Wong TY (2012) Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep 12: 346-354.
  61. Wu M, Chen Y, Wilson K, Chirindel A, Ihnat MA, et al. (2008) Intraretinal leakage and oxidation of LDL in diabetic retinopathy. Invest Ophthalmol Vis Sci 49: 2679-2685.
  62. Zou MH, Li H, He C, Lin M, Lyons TJ, et al. (2011) Tyrosine nitration of prostacyclin synthase is associated with enhanced retinal cell apoptosis in diabetes. Am J Pathol 179: 2835-2844.
  63. Barber AJ, Antonetti DA, Kern TS, Reiter CE, Soans RS, et al. (2005) The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest Ophthalmol Vis Sci 46: 2210-2218.
  64. Han Z, Guo J, Conley SM, Naash MI (2013) Retinal angiogenesis in the Ins2(Akita) mouse model of diabetic retinopathy. Invest Ophthalmol Vis Sci 54: 574-584.
  65. COGAN DG, TOUSSAINT D, KUWABARA T (1961) Retinal vascular patterns. IV. Diabetic retinopathy. Arch Ophthalmol 66: 366-378.
  66. Kern TS, Engerman RL (1995) Vascular lesions in diabetes are distributed non-uniformly within the retina. Exp Eye Res 60: 545-549.
  67. Lyons TJ, Li W, Wells-Knecht MC, Jokl R (1994) Toxicity of mildly modified low-density lipoproteins to cultured retinal capillary endothelial cells and pericytes. Diabetes 43: 1090-1095.
  68. Song W, Barth JL, Yu Y, Lu K, Dashti A, et al. (2005) Effects of oxidized and glycated LDL on gene expression in human retinal capillary pericytes. Invest Ophthalmol Vis Sci 46: 2974-2982.
  69. Itabe H, Obama T, Kato R (2011) The Dynamics of Oxidized LDL during Atherogenesis. J Lipids 2011: 418313.
  70. Song W, Barth JL, Lu K, Yu Y, Huang Y, et al. (2005) Effects of modified low-density lipoproteins on human retinal pericyte survival. Ann N Y Acad Sci 1043: 390-395.
  71. Diffley JM, Wu M, Sohn M, Song W, Hammad SM, et al. (2009) Apoptosis induction by oxidized glycated LDL in human retinal capillary pericytes is independent of activation of MAPK signaling pathways. Mol Vis 15: 135-145.
  72. Fu D, Wu M, Zhang J, Du M, Yang S, et al. (2012) Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. Diabetologia 55: 3128-3140.
  73. Lyons TJ, Li W, Wojciechowski B, Wells-Knecht MC, Wells-Knecht KJ, et al. (2000) Aminoguanidine and the effects of modified LDL on cultured retinal capillary cells. Invest Ophthalmol Vis Sci 41: 1176-1180.
  74. Muller C, Salvayre R, Nègre-Salvayre A, Vindis C (2011) Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: prevention by HDLs. Autophagy 7: 541-543.
  75. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820.
  76. Zhang SX, Wang JJ, Dashti A, Wilson K, Zou MH, et al. (2008) Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein. J Mol Endocrinol 41: 135-143.
  77. Jenkins AJ, Li W, Moller K, Klein RL, Fu MX, et al. (1999) Pre-enrichment of modified low density lipoproteins with alpha-tocopherol mitigates adverse effects on cultured retinal capillary cells. Curr Eye Res 19: 137-145.
  78. Zhou T, Zhou KK, Lee K, Gao G, Lyons TJ, et al. (2011) The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy. Diabetologia 54: 459-468.
  79. Lupo G, Anfuso CD, Ragusa N, Strosznajder RP, Walski M, et al. (2001) t-Butyl hydroperoxide and oxidized low density lipoprotein enhance phospholipid hydrolysis in lipopolysaccharide-stimulated retinal pericytes. Biochim Biophys Acta 1531: 143-155.
  80. Panini SR, Yang L, Rusinol AE, Sinensky MS, Bonventre JV, et al. (2001) Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized LDL/oxysterol. J Lipid Res 42: 1678-1686.
  81. Ozaki M, Yamada Y, Matoba K, Otani H, Mune M, et al. (1999) Phospholipase A2 activity in ox-LDL-stimulated mesangial cells and modulation by alpha-tocopherol. Kidney Int Suppl 71: S171-173.
  82. Norata GD, Pirillo A, Pellegatta F, Inoue H, Catapano AL (2004) Native LDL and oxidized LDL modulate cyclooxygenase-2 expression in HUVECs through a p38-MAPK, NF-kappaB, CRE dependent pathway and affect PGE2 synthesis. Int J Mol Med 14: 353-359.
  83. Sennlaub F, Valamanesh F, Vazquez-Tello A, El-Asrar AM, Checchin D, et al. (2003) Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy. Circulation 108: 198-204.
  84. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, et al. (2002) Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 16: 438-440.
  85. Chew EY, Kim J, Coleman HR, Aiello LP, Fish G, et al. (2010) Preliminary assessment of celecoxib and microdiode pulse laser treatment of diabetic macular edema. Retina 30: 459-467.
  86. Barth JL, Yu Y, Song W, Lu K, Dashti A, et al. (2007) Oxidised, glycated LDL selectively influences tissue inhibitor of metalloproteinase-3 gene expression and protein production in human retinal capillary pericytes. Diabetologia 50: 2200-2208.
  87. Klouche M, Peri G, Knabbe C, Eckstein HH, Schmid FX, et al. (2004) Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells. Atherosclerosis 175: 221-228.
  88. Rolph MS, Zimmer S, Bottazzi B, Garlanda C, Mantovani A, et al. (2002) Production of the long pentraxin PTX3 in advanced atherosclerotic plaques. Arterioscler Thromb Vasc Biol 22: e10-14.
  89. Li J, Wang JJ, Yu Q, Wang M, Zhang SX (2009) Endoplasmic reticulum stress is implicated in retinal inflammation and diabetic retinopathy. FEBS Lett 583: 1521-1527.
  90. Jing G, Wang JJ, Zhang SX (2012) ER stress and apoptosis: a new mechanism for retinal cell death. Exp Diabetes Res 2012: 589589.
  91. Wu M, Yang S, Elliott MH, Fu D, Wilson K, et al. (2012) Oxidative and endoplasmic reticulum stresses mediate apoptosis induced by modified LDL in human retinal Muller cells. Invest Ophthalmol Vis Sci 53: 4595-4604.
  92. Oshitari T, Hata N, Yamamoto S (2008) Endoplasmic reticulum stress and diabetic retinopathy. Vasc Health Risk Manag 4: 115-122.
  93. Chen Y, Hu Y, Zhou T, Zhou KK, Mott R, et al. (2009) Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models. Am J Pathol 175: 2676-2685.
  94. Du M, Wu M, Fu D, Yang S, Chen J, et al. (2013) Effects of modified LDL and HDL on retinal pigment epithelial cells: a role in diabetic retinopathy? Diabetologia 56: 2318-2328.
  95. Plafker SM, O'Mealey GB, Szweda LI (2012) Mechanisms for countering oxidative stress and damage in retinal pigment epithelium. Int Rev Cell Mol Biol 298: 135-177.
  96. Xu HZ, Song Z, Fu S, Zhu M, Le YZ (2011) RPE barrier breakdown in diabetic retinopathy: seeing is believing. J Ocul Biol Dis Infor 4: 83-92.
  97. Gordiyenko N, Campos M, Lee JW, Fariss RN, Sztein J, et al. (2004) RPE cells internalize low-density lipoprotein (LDL) and oxidized LDL (oxLDL) in large quantities in vitro and in vivo. Invest Ophthalmol Vis Sci 45: 2822-2829.
  98. Picard E, Houssier M, Bujold K, Sapieha P, Lubell W, et al. (2010) CD36 plays an important role in the clearance of oxLDL and associated age-dependent sub-retinal deposits. Aging (Albany NY) 2: 981-989.
  99. Hoppe G, Marmorstein AD, Pennock EA, Hoff HF (2001) Oxidized low density lipoprotein-induced inhibition of processing of photoreceptor outer segments by RPE. Invest Ophthalmol Vis Sci 42: 2714-2720.
  100. Hoppe G, O'Neil J, Hoff HF, Sears J (2004) Accumulation of oxidized lipid-protein complexes alters phagosome maturation in retinal pigment epithelium. Cell Mol Life Sci 61: 1664-1674.
  101. Yu AL, Lorenz RL, Haritoglou C, Kampik A, Welge-Lussen U (2009) Biological effects of native and oxidized low-density lipoproteins in cultured human retinal pigment epithelial cells. Exp Eye Res 88: 495-503.
  102. Yin L, Wu X, Gong Y, Shi Y, Qiu Y, et al. (2011) OX-LDL up-regulates the vascular endothelial growth factor-to-pigment epithelium-derived factor ratio in human retinal pigment epithelial cells. Curr Eye Res 36: 379-385.
  103. Yin L, Shi Y, Liu X, Zhang H, Gong Y, et al. (2012) A rat model for studying the biological effects of circulating LDL in the choriocapillaris-BrM-RPE complex. Am J Pathol 180: 541-549.
  104. Moreira EF, Larrayoz IM, Lee JW, Rodríguez IR (2009) 7-Ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation. Invest Ophthalmol Vis Sci 50: 523-532.
Citation: Yu JY, Lyons TJ (2013) Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina. J Clin Exp Ophthalmol 4:314.

Copyright: © 2013 Yu JY, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.