Vitamin E And Pkc Inhibition

Oxidative stress has been postulated as an underlying cause of diabetic vascular complications (108-112). Antioxidants such as vitamin E have been the subject of considerable interest with respect to their potential ability to ameliorate diabetic complications. There has also been considerable interest in the use of vitamin E as an antioxidant agent for potential beneficial effects in coronary disease and cancers. Results from large multicenter clinical trials are now becoming available. A study on coronary heart disease in women (113) and in men (114) showed that increased vitamin E intake was associated with a significant risk reduction for coronary heart disease. Additionally, a recently published study involving male smokers in Finland (115) showed a 32% decrease in the incidence of prostate cancer in subjects taking 50 mg vitamin E/day. Interestingly, in this study there was a 23% increase in prostate cancer in those subjects randomized to P-carotene. Clinical studies aimed at characterizing the effect of vitamin E in the eye have focused primarily on the potential benefit of vitamin E in age-related macular degeneration (116,117), retinitis pigmentosa (118), and retinopathy of prematurity (119). The results from these studies are suggestive that vitamin E specifically and other antioxidants in general may be beneficial in treating macular degeneration and retinopathy of prematurity. There have been, however, no clinical studies aimed at investigating the effect of vitamin E in diabetes.

In the rat retina, vitamin E levels were fivefold higher than in other tissues such as the aorta (120). Vitamin E supplementation further increased these retinal vitamin E levels. Other investigators have shown that vitamin E is present in primate and human retinas (121-123), that the regional retinal distribution of vitamin E suggests an antioxidant protective effect against age-related macula degeneration, and that the level of vitamin E in the retina correlates with serum vitamin E levels (121).

Vitamin E, in addition to its antioxidant potential, has the other interesting property of being effective in inhibiting the activation of the DAG-PKC pathway in vascular tissues and cultured vascular cells exposed to high glucose levels (32,120). When retinal vascular endothelial cells exposed to high glucose were treated with vitamin E (¿/-«-tocopherol), DAG decreased and PKC activation was normalized (32,120). We reported that vitamin E can inhibit PKC activation, probably by decreasing DAG levels (32,120), because the direct addition of vitamin E to purified PKC a or p isoforms in vitro did not have any inhibitory effect (120). These results are consistent with other studies demonstrating that ¿/-«-tocopherol will inhibit PKC activation (124-126). Boscoboinik et al. (124) first demonstrated in 1991 that PKC activation was inhibited by ¿/-«-tocopherol in a manner unrelated to ¿/-«.-tocopherol's antioxidant action (124-127). They also showed that the magnitude of the inhibition was related to the level of PKC activation (128) with little effect of d-a-tocopherol if cellular PKC was not activated.

Recently, the activation of DAG kinase has been suggested to be one potential site of action for vitamin E to inhibit PKC. Results indicate an indirect effect through activation of DAG kinase and increased metabolic break down of DAG to phosphatidic acid that resulted in decreased DAG levels and decreased PKC activation (129). Koya et al. (130) confirmed these results in the kidney and showed that glomerular dysfunction in diabetic rats could be prevented by ¿/-«-tocopherol treatment through PKC inhibition, most likely mediated through increased DAG kinase activity.

In vivo studies in the diabetic rat have shown that the decreased retinal blood flow is related to elevation of retinal DAG levels, inhibition of DAG kinase (131), and the activation of PKC (16,32), particularly the (3 isoform of PKC (19,131). The results from these studies showed that the effects of increased DAG levels and PKC activation on retinal hemodynamics in nondia-betic rats can mimic the hemodynamic changes measured in untreated diabetic rats.

In diabetic rats, vitamin E treatment through regular intraperitoneal injections prevented the increases in both DAG levels and the activation of PKC in the retina, aorta, heart, and renal glomeruli (120,131). Functionally, vitamin E treatment prevented the abnormal hemodynamics in retina and kidney of diabetic rats in parallel with the inhibition of DAG-PKC activation (120,131). In addition, increased albuminuria was prevented by vitamin E treatment in diabetic rats (131). Normalization of the physiological parameters studied in these diabetic rats was achieved despite chronically maintained elevated blood glucose levels. Thus, it is possible that some of the PKC activation induced by diabetes could also be the result of excessive oxidants, which are known to activate PKC and can be produced by hyperglycemia, leading to the development of vascular dysfunction in the early stages of diabetes (132).

In diabetic patients with no or minimal diabetic retinopathy, retinal blood flow was reduced to an extent comparable with that measured in diabetic rats (35,37). Studies have shown that the reduction in retinal blood flow in these patients is associated with the level of glycemic control (35). These clinical results combined with prior animal studies provide the support for performing clinical studies aimed at evaluating whether vitamin E treatment is also effective in normalizing retinal blood flow and renal function in patients with IDDM. Additionally, multicenter clinical trials will need to be initiated to answer the question of whether high doses of vitamin E can prevent the development of microvascular complications in diabetes.

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