Aldose Reductase Regulates Reactive Oxygen Species Mediated

Chapter 15

Aldose Reductase Regulates Reactive Oxygen Species Mediated-Inflammatory Signals Kota V. Ramana , Deepak Chandra , Sanjay Srivastava , A r u n i Bhatnagar , Bharat B. Aggarwal , and Satish K. Srivastava

Downloaded by PENNSYLVANIA STATE UNIV on July 18, 2012 | http://pubs.acs.org Publication Date: October 13, 2003 | doi: 10.1021/bk-2003-0865.ch015

1

2

1

2

3

1

Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555 Division of Cardiology, Department of Medicine, University of Louisville, Louisville, KY 40202 Cytokine Research Laboratory, Department of Bioimmunotherapy, M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030

1

2

3

Aldose reductase (AKR1B1, abbreviated as AR) is an aldoketo reductase (AKR) that catalyzes the reduction of glucose to sorbitol, which is the first and rate-limiting step of the polyol pathway. The enzyme is also efficient in reducing multiple lipid peroxidation-derived aldehydes and their glutathione conjugates. However, the physiological significance of AR catalysis in intracellular signaling and cell cycle regulation has not been assessed. Our recent observations suggest that A R mediates the mitogenic and cytotoxic signals of reactive oxygen species generated by growth factors as well as cytokines. The mitogenic role of AR is supported by the observations that inhibition of AR attenuates TNF-α, PDGF or bFGF, but not phorbol ester (PMA)-mediated activation of the redox-sensitive transcription factors - N F - ĸ B and AP1. In vivo, these stimuli are key regulators of vascular smooth muscle cell proliferation and apoptosis of vascular endothelial cells. Pretreatment with A R inhibitors also prevented the activation of protein

© 2004 American Chemical Society In Aldo-Keto Reductases and Toxicant Metabolism; Penning, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

213

214


kinase C (PKC) induced by TNF-α, bFGF, and PDGF but not PMA, indicating that inhibition of the P K C / N F - ĸ B pathway may be a significant cause of the anti-inflammatory effects of AR inhibitors. Collectively, these observations suggest that AR may be a critical and essential mediator of vascular inflammation and that it may be required to facilitate multiple signaling events regulating cell cycle progression and apoptosis.

Oxidative and Antioxidant Roles of Aldose Reductase Accumulating evidence demonstrating that the inhibition of aldose reductase (AKR1B1, abbreviated as AR) prevents or delays hyperglycemic injury in experimental models of diabetes, supports the view that A R is etiologically involved in the development of secondary diabetic complications such as cataractogenesis, retinopathy, neuropathy, nephropathy and microangiopathy (1-6). Based on this evidence, it has been proposed that the increased flux of glucose via AR causes osmotic and oxidative changes, which in turn, trigger a sequence of metabolic changes resulting in gross tissue dysfunction, altered intracellular signaling, and extensive cell death (1,2). Thus, during hyperglycemia, AR could induce oxidative stress due to a decrease in the NADPH/NADP ratio caused by the reduction of excessive glucose to sorbitol (5,6). This oxidative stress could be intensified further by subsequent metabolism of sorbitol to fructose via sorbitol dehydrogenase, which converts NADH to N A D , thereby inducing a state of chemical hypoxia. Our previous work shows that, in addition to glucose, AR also catalyzes the reduction of lipid peroxidation-derived aldehydes and their glutathione (GSH) conjugates (7-9). The purified enzyme displays high affinity for these aldehydes and their conjugates. In isolated perfused hearts, erythrocytes, cultured vascular smooth muscle cells (VSMC), and vascular endothelial cells (VEC), inhibition of AR prevents the reduction of glutathiolated aldehydes (10-12). Because these aldehydes, particularly the ct,P-unsaturated alkenals such as 4-hydroxy trans 2nonenal (HNE) are highly reactive and cytotoxic (13), their metabolism via AR may be an antioxidant defense mechanism, at least under euglycemic conditions. The antioxidant role of AR is consistent with the observations that in a variety of cell types, A R is upregulated by several oxidants such as hydrogen peroxide (14), methyl glyoxal (15), and nitric oxide (16), and during pathological conditions associated with oxidative stress, such as myocardial ischemia and reperfiision (17). The expression of AR is also enhanced upon exposure to its substrates such as HNE (14) suggesting that conditions associated with high accumulation of electrophiles lead to induction of the AR gene. +

+

In Aldo-Keto Reductases and Toxicant Metabolism; Penning, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

215 Several lines of experimental evidence suggest that up-regulation of AR by oxidative stress may be a protective response. The expression of AR in VSMC, for example, is increased by H 0 or HNE stimulation and inhibition of the enzyme increases the sensitivity of these cells to both H 0 and HNE -mediated cell death (14). An in vivo correlation to these observations is provided by Rittner et aL, who demonstrate that during giant cell arteritis, elevated levels of AR are associated with the proliferative intima and with areas of high positive immunoreactivity with anti-protein-HNE antibodies (18). Interestingly, AR inhibitors increased HNE accumulation in this model and caused a 4-fold elevation of apoptotic cells in the vascular lesions. These data suggest that increased A R activity may be specifically associated with areas of high inflammation or growth and that the activity of this enzyme may be essential for cell cycle progression. Because in vascular tissues, redox signaling is a significant component of these events (inflammation, cell growth and survival), we examined whether changes in the AR activity affect proinflammatory responses or apoptosis. 2

2


2

2

Aldose Reductase Mediates the Mitogenic and the Cytotoxic Signals A mitogenic role of AR is suggested by our observation that treatment with AR inhibitors diminishes the extent of neointimal hyperplasia in the ballooninjured rat carotid arteries (19). Furthermore, the involvement of AR in mediating cell growth and survival is supported by the results of our cell culture studies showing that inhibition of this enzyme by structurally distinct inhibitors prevents the proliferation of VSMC and the apoptosis of VEC in response to TNF-a and growth factors. High levels of growth factors and cytokines are expressed in the intimal lesions in vivo and these mediators have been shown to play a critical role in the progression of atherosclerosis and restenosis (20-22). In restenotic vessels, TNF-a is the most abundant cytokine and intimal proliferation of VSMC has been linked to increased TNF-a stimulation. The mitogenic role of TNF-a in vascular lesions is in contrast to its well-known proapoptotic activity seen with several cell types in culture. Hence, because of its central role in mediating vascular inflammation and abnormal growth, we examined the effects of TNF-a on VSMC proliferation in culture and tested whether this paradigm of VSMC growth depends on AR. When serum-starved rat aortic VSMC were stimulated with TNF-a in culture a two-fold increase in cell growth was observed within 24 h (Figure 1). This is consistent with previous reports documenting the proliferative activity of TNF-a with VSMC in culture (23,24). However, when the serum-starved cells were pre-incubated with AR inhibitors, sorbinil or tolrestat, 12 to 24 h before TNF-a stimulation, a significant prevention of TNFa-induced proliferation was observed. Neither of the A R inhibitors affected cell growth by itself, i.e., in the absence of TNF-a

In Aldo-Keto Reductases and Toxicant Metabolism; Penning, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

216


stimulation. These data clearly demonstrate that inhibition of AR prevents TNFot-induced VSMC growth in culture (Figure 1).

Figure L Aldose reductase inhibitors attenuate TNF-a-induced VSMC proliferation *P

Aldose Reductase Regulates Reactive Oxygen Species Mediated

Recommend Documents