【摘要】 糖尿病性视网膜病变（diabetic retinopathy,DR）是糖尿病最常见且严重的微血管并发症之一，其发病机制复杂，是多因素、多阶段作用的结果。近年研究表明，DR的发生与氧化应激密切相关，抗氧化治疗有助病情改善。血红素氧合酶1(heme oxygenase1,HO1)是一种广泛存在的抗氧化防御酶，可对抗氧化应激造成的损伤，具有重要的生理作用。研究表明，在高血糖环境中，视网膜内HO1的表达被诱导增高，且通过人为调节HO1的表达水平可以加速或延缓病情的进展，提示将HO1应用于DR的诊治有良好的应用前景。本文从氧化应激的角度对二者加以概述。
【关键词】 糖尿病性视网膜病变；氧化应激；血红素氧合酶1
AbstractDiabetic retinopathy is one of the most common and serious microvascular complications of diabetes, and it is a very complex pathological process, displaying multifactor, multistage characteristic in the outcome. Recent studies have shown that the pathogenesis of diabetic retinopathy is closely related to oxidative stress, and antioxidant therapy can effectively improve the condition. Heme oxygenase1(HO1)is a widely existing antioxidant defense enzyme, which can reduce the injury caused by oxidative stress and plays an important physiological role. Studies have indicated that in retina HO1 can be highly induced by hyperglycemia. Moreover, the expression level of HO1 by manmade changes can accelerate or postpone the diseases progression. That means HO1 for the diagnosis and treatment of diabetic retinopathy has satisfactory applied foreground. In this article we would like to review the role of HO1 in diabetic retinopathy.
KEYWORDS：diabetic retinopathy; oxidative stress; heme oxygenase1
INTRODUCTION
Diabetic retinopathy is one of the most common and serious microvascular complications of diabetes. Recently the incidence of diabetic retinopathy significantly turns higher, and diabetic retinopathy has become one of the four major blindnesscausing diseases[1,2].Diabetic retinopathy is a very complex pathological process, which displays multifactor, multistage characteristic in the outcome. A more unanimous view is that chronic hyperglycemia is the basis of pathogenesis, and microangiopathy is the key to the pathological changes. In the development of diabetic retinopathy oxidative stress plays a very important role.
Heme oxygenase1 (HO1), an important part of the human defense mechanisms, has been recognized to have significant functions, including antioxidative stress, antiproliferation of cells, antiapoptosis, suppressing platelet aggregation, etc. In recent years, the effect of HO1 in antioxidative stress was gradually affirmed and become a new hotspot. This view will focus on diabetic retinopathy and HO1 from the perspective of oxidative stress.
OXIDATIVE STRESS IN DIABETES
Under normal physiological conditions, approximately 0.1%5% of oxygen that enters the electron transport chain is reduced to superoxide; reactive oxygen species (ROS) and the rest are used in metabolic processes. ROS are produced continuously in all cells to support normal cellular functions. However, excess production of ROS originated from endogenous or exogenous sources, or inefficient removal of ROS, could result in pathological conditions. ROS produced during normal oxidative metabolism are eliminated by an efficient scavenging system, but under pathological conditions an imbalance between production and elimination of ROS can result in an excessive level of either molecular oxygen or ROS, thus leading to increased "oxidative stress". Hence, oxidative stress is the cytopathic consequence of the generation of excessive ROS beyond the capacity of a cell to defend against them, and represents an imbalance between excessive formation and/or impaired removal of ROS.
Consequences of chronic oxidative stress include damage to biological macromolecules such as DNA, lipids, proteins, and carbohydrates, disruption in cellular homeostasis,and generation of other ROS creating further damage which results in many disease processes of clinical interest[3].Diabetes is shown to increase oxidative stress both in humans and animals[46]and increased oxidative stress is postulated to play an important role in the pathogenesis of diabetic complications[69]. Hyperglycemia has been demonstrated to increase oxidative stress which is associated with specific biochemical changes, including protein kinase C (PKC) activation, the nonenzymatic glycation of proteins and increased polyol pathway activity[10,11],all of which contribute to diabetes. The possible sources of oxidative stress in diabetes might include 1)increased generation of ROS by autooxidation of glucose; 2)shifts in redox balances; 3)impaired activities of antioxidant defense enzymes such as superoxide dismutase (SOD)and catalase; 4)decreased tissue concentrations of low molecular weight antioxidants such as reduced glutathione (GSH) and vitamin E[8,12].
OXIDATIVE STRESS AND DIABETIC RETINOPATHY
The retina is unique. The outer retina is avascular and receives its oxygen supply from the choroid, which lacks hyperoxiainduced autoregulation. Therefore, photoreceptors are exposed to higher level of tissue oxygen than most other tissue[13]. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, high proportion of polyunsaturated fatty acids, and exposure to visible light [13,14]. It has been suggested that the correlation between hyperglycemia, changes in the redox homeostasis, and oxidative stress is the key event in the pathogenesis of diabetic retinopathy. Oxidative stress can influence the expression of multiple genes,including signaling molecules; overexpression of these genes may cause mitochondrial dysfunction and peroxidization of the lipid and protein structure, which induce a variety of cellular dysfunctions leading to retinopathy[1520].
Animal studies have demonstrated that oxidative stress contributes not only to the development of diabetic retinopathy but also to the resistance of retinopathy to reversion after good glycemic control is reinstituted—the metabolic memory phenomenon[21]. Superoxide levels are elevated in the retina of diabetic rats and in retinal cells incubated in high glucose media[2224], and hydrogen peroxide content is increased in the retina of diabetic rats[25].On the contrast, the activities of antioxidant defense enzymes responsible for scavenging free radicals and maintaining redox homeostasis such as SOD, glutathione reductase, glutathione peroxidase, and catalase are diminished in the retina[8,12].
Furthermore, the cell is equipped with intracellular antioxidant, GSH,which is probably the most important defense the cell is equipped with. It can act as a ROS scavenger and modulate intracellular redox state [26]. The level of this intracellular antioxidant is decreased in the retina in diabetes[27],and the enzymes responsible for its metabolism are compromised[28,29]. Apart from the antioxidant defense enzymes, nonenzymic antioxidants such as vitamin C, vitamin E, and βcarotene that exist biologically for the regulation of redox homeostasis are also depressed during hyperglycemiainduced oxidative stress[30].
The possible mechanism of oxidative stress leading to diabetic retinopathy might include: 1)Free radicals directly react with lipids and proteins: free radicals attack the retinal capillary basement membrane phospholipids, which may cause peroxidization of lipids, consequentely leading to the incease of vascular permeability. Plasma proteins deposit on the capillary basement membrane, which makes the basement membrane thickening. 2) Lipid peroxidation products can promote thromboxane A2 (TXA2) synthesis, decrease prostaglandin I2(PGI2) synthesis and cause platelet aggregation, vasoconstriction and thrombosis formation. 3) Lowdensity lipoprotein (LDL)when attacked by free radicals, generating strong cytotoxic oxidative low density lipoprotein (oxLDL), which can directly damage capillary endothelial cells and increase the adhesion molecule expression and capillary leakage. Moreover, endothelial cell damage may cause capillary occlusion. 4) Lipid peroxidation can enhance the adhesion of erythrocytes on endothelial cell and degrade deformation ability, which contribute to the changes of retinal blood flow. Oxidative stress and free radical products can directly attack DNA, causing dysfunction cell differentiating, proliferation cycle extending and apoptosis. Exposed to OxLDL, the endothelial cells can reduce 41%, and the pericytes decease 25%[31].
HEME OXYGENASE1
Heme oxygenase (HO), originally identified by Tenhunen et al[32], is a rate limiting enzyme in heme catabolization, which catabolizes heme to carbon monoxide (CO), free iron, and biliverdin(BV). Biliverdin is subsequently converted to bilirubin(BR) by the enzyme biliverdin reductase[32,33]. HO is represented by three isoforms: HO1, HO2, and HO3, encoded by separate genes. Among the three isoforms of HO[34], HO1 is an inductive isoform and is induced by oxidative stress, ultraviolet irradiation, ischemiareperfusion, heavy metals, cytokines, and nitric oxide[3537]. HO1 belongs to the heatshock protein family and functions as anantioxidant, an antiapoptotic agent, cytoprotective agent, and antiinflammatory agent under different pathologic conditions[35,3840].Oxidative stress, in particular, appears to be a major factor in HO1 induction under pathologic conditions [4143] .
HO1 has been demonstrated both in vitro and in vivo in various mammalian cells and organs[4446]. Many cells in culture, including hemopoietic, hepatic, epithelial and endothelial cells, respond to oxidative agents by a marked increase of HO1 activity[47,48].Several studies have shown that induction of HO1 in vitro and in vivo appears to provide protection for cells and tissues from subsequent oxidative stress[4953], whereas inhibition of HO1 expression results in cell and tissue damage[54].
Under conditions of oxidative stress, HO1 manifests itself as an antioxidative defense factor. It is suggested that the antioxidative effect of HO1 is associated with the production of bilirubin, an effective free radical scavenger[43], and bilirubin is able to react with the superoxide anion and peroxyradicals. HO reaction also generates Fe2+, an agent that is deleterious to the cell. It is thought, however, that this in turn leads to the induction of ferritin, which could sequester free Fe2+ [55].Thus, the expression level of HO1 in a given cell/tissue can serve as an index of the ability of these cells to protect themselves from oxidative injury. Recently, it has been demonstrated that both the neural retina and retinal pigment epithelium (RPE) contain the HO1 isoenzyme protein and mRNA[56,57].
The present study shows that HO1 is activated in neural retina due to diabetes and may present a protective response by quenching free radical toxicity or by potentiallyincreasing bilirubin levels[58,59]. Another study shows that HO1 could play an protective role in the survival of M ller cells, which are specialized glial cells found only in the retina[60]. Increased retinal HO1 mRNA expression in diabetic rats has been shown to be prevented with antioxidant therapy[61],and HO1 overexpression cells have shown the reduced level of apoptosis[62].In contrast,others have found diminished HO1 mRNA expression in RPE cells from diabetic donors. The difference for such discrepancy is not clear,but it is possible that the results may contribute to the vulnerability of the retinal parenchyma to significant metabolic alterations encountered in the diabetic state[63].So further investigation is needed to understand the functional role of HO1 in the retina.
In summary, most studies strongly suggest that oxidative stress could play a crucial role in the development ofdiabetic retinopathy, and antioxidant supplementation inhibits its proceeding. HO1, as a widey existing antioxidantdefence, can reduce the injury caused by oxidative stress, although the exact mechanism of HO1 remains unclear.For guiding future therapeutic studies it is necessary to demonstrate the link between diabetic retinopathy and HO1.This remains an area where much needs to be done.
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