NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 10 pptx

NOVEL CELLULAR PATHWAYS 528 The local RAS is activated under diabetes (Anderson 1997). We have recently found that angiotensin II (Ang II) stimulated intracellular ROS generation in retinal pericytes through an interaction with type 1 receptor. Further, Ang II decreased DNA synthesis and simultaneously upregulated VEGF mRNA levels in pericytes, both of which were blocked by treatment with telmisartan, a com- mercially available Ang II type 1 receptor blocker, or an antioxidant NAC (Yamagishi, Amano, Inagaki et al. 2003; Amano, Yamagishi, Inagaki et al. 2003). These results suggest that Ang II-type 1 receptor interaction could induce pericyte loss and dysfunction through intracellular ROS generation, thus being involved in diabetic retinopathy. Since Ang II induces the VEGF receptor, KDR, expression in retinal microvascular ECs, the retinal RAS might aug- ment the permeability- and angiogenesis-inducing activity of VEGF, thus implicated in the progression of diabetic retinopathy as well (Otani, Takagi, Suzuma et al. 1998). Blockade of the RAS by inhibitors of angiotensin converting enzyme or Ang II type 1 receptor antag- onists can reduce retinal overexpression of VEGF and hyperpermeability and neovascularization in experimental diabetes (Babaei-Jadidi, Karachalias, Ahmed et al. 2003; Anderson 1997; Yamagishi, Amano, Inagaki et al. 2003). Funatsu et al. (Funatsu, Yamashita, Nakanishi et al. 2002) recently found that the vitreous  uid level of Ang II was signi cantly correlated with that of VEGF, and both of them were signi cantly higher in patients with active proliferative diabetic retinopathy than in those with qui- escent proliferative diabetic retinopathy (Amano, Yamagishi, Inagaki et al. 2003). These  ndings further support the concept that Ang II contributes to development and progression of proliferative diabetic retinopathy in combination with VEGF. In the EUCLID Study, the angiotensin-converting enzyme inhibitor, lisinopril, reduced the risk of progression of retinopathy by approximately 50% and also signi cantly reduced the risk of progression to proliferative retinopathy although retinopathy was not a primary end point and the study was not suf ciently powered for eye-related outcomes (Otani, Takagi, Suzuma et al. 1998). The interaction of the RAS and AGE–RAGE system has also been proposed. We have found that Ang II potentiates the deleterious effects of AGEs on pericytes by inducing RAGE protein expression (Yamagishi, Takeuchi, Matsui et al. 2005). In vivo, AGE injection stimulated RAGE expression in the eye of spontaneously hypertensive rats, which was blocked by telmisartan. In vitro, Ang II-type 1 receptor- mediated ROS generation elicited RAGE gene expression in retinal pericytes through NF-κB the characteristic changes of the early phase of diabetic retinopathy, in streptozotocin-induced diabetic rats. These observations suggest that SDH-mediated conversion of sorbitol into fructose and the resultant ROS generation may play a role in the pathogenesis of diabetic retinopathy. Since fructose is a stronger gly- cating agent than glucose, intracellular AGEs formation via the SDH pathway might be involved in glucose toxicity to retinal pericytes (Rosen, Nawroth, King et al. 2001). There is a growing body of evidence that generation of ROS is increased in diabetes. High glucose concentrations, via various mechanisms such as glucose autoxidation, increased the production of AGEs, activation of PKC, and stimulation of the polyol pathway, and it enhanced ROS generation (Rosen, Nawroth, King et al. 2001; Bonnefont- Rousselot 2002). Increased ROS generation has been found to regulate vascular in ammation, altered gene expression of growth factors and cytokines, and platelet and macrophage activation, thus playing a central role in the pathogenesis of diabetic vascular complications (Yamagishi, Edelstein, Du et al. 2001; Yamagishi, Edelstein, Du et al. 2001; Yamagishi, Okamoto, Amano et al. 2002; Spitaler, Graier 2002; Yamagishi, Inagaki, Amano et al. 2002; Yamagishi S, Amano S, Inagaki et al. 2003). Further, we have recently found that high glucose–induced mitochondrial overproduction of superoxide serves as a causal link between elevated glucose and hyperglycemic vascular damage in ECs (Nishikawa, Edelstein, Du et al. 2000; Brownlee 2001). Normalizing levels of mitochondrial ROS prevent glucose-induced formation of AGEs, activation of PKC, sorbitol accumulation, and NF-κB activation. These observations suggest that the three main mechanisms implicated in the pathogenesis of diabetic vascular complications might re ect a single hyperglycemia-induced process, thus providing a novel therapeutic target for diabetic angiopathies. Recently, Hammes et al. (Hammes, Du, Edelstein et al. 2003) have dis- covered that the lipid-soluble thiamine derivative benfotiamine can inhibit the three major biochemical pathways as well as hyperglycemia-associated NF-κB activation (Hammes, Du, Edelstein et al. 2003). They showed that benfotiamine prevented experimental diabetic retinopathy by activating the pentose phosphate pathway enzyme, transketo- lase, in the retinas, which converts glyceraldehyde- 3-phosphate and fructose-6-phosphate into pentose- 5-phosphates and other sugars (Hammes, Du, Edelstein et al. 2003). Thiamine and benfotiamine therapy is reported to prevent streptozotocin-induced incipient diabetic nephropathy as well (Babaei-Jadidi, Karachalias, Ahmed et al. 2003). Chapter 21: Diabetic Vascular Complications 529 (Cooper, Bonnet, Old eld et al. 2001). Evidence has implicated the TGF-β system as a major etiologic agent in the pathogenesis of glomerulosclerosis and tubulointerstitial  brosis in diabetic nephropathy (Sharma, Ziyadeh 1995; Aoyama, Shimokata, Niwa 2000; Wang, LaPage, Hirschberg 2000). AGEs induce apoptotic cell death and VEGF expression in human-cultured mesangial cells, as the case in pericytes (Yamagishi, Inagaki, Okamoto et al. 2002). Mesangial cells occupy a central ana- tomical position in the glomerulus, playing crucial roles in maintaining structure and function of glomerular capillary tufts (Dworkin, Ichikawa, Brenner 1983). They actually provide structural support for capillary loops and modulate glomerular  ltration by its smooth muscle activity (Dworkin, Ichikawa, Brenner 1983; Kreisberg, Venkatachalam, Troyer 1985; Schlondorff 1987). Therefore, it is conceivable that the AGE-induced mesangial apoptosis and dysfunction may contribute in part to glomerular hyper-  ltration, an early renal dysfunction in diabetes. Several experimental and clinical studies support the pathological role for VEGF in diabetic nephropathy. Indeed, antibodies against VEGF have been found to improve hyper ltration and albuminuria in streptozotocin-induced diabetic rats (De Vriese, Tilton, Elger et al. 2001). Inhibition of VEGF also prevents glomerular hypertrophy in a model of obese type 2 diabetes, the Zucker diabetic fatty rat (Schrijvers, Flyvbjerg, Tilton et al. 2006). Further, urinary VEGF levels are positively correlated with the urinary albumin to creatinine ratio and negatively correlated with creatinine clearance in type 2 diabetic patients (Kim, Oh, Seo et al. 2005). These observations suggest that urinary VEGF might be used as a sensitive marker of diabetic nephropathy. VEGF overproduction elicited by AGEs may be involved in diabetic nephropathy. Moreover, we have recently found that AGE–RAGE interaction stimulates MCP-1 expression in mesangial cells through ROS generation (Yamagishi, Inagaki, Okamoto et al. 2002). Increased MCP-1 expression associated with monocyte in ltration in mesangium has been observed in the early phase of diabetic nephropathy as well (Banba, Nakamura, Matsumura et al. 2000). Plasma MCP-1 was positively correlated with urinary albumin excretion rate in type 1 diabetic patients (Chiarelli, Cipollone, Mohn et al. 2002). AGE accumulation in glomerulus could also be implicated in the initiation of diabetic nephropathy by promot- ing the secretion of MCP-1. AGE formation on extracellular matrix proteins alters both matrix–matrix and cell–matrix interactions, involved in the pathogenesis of diabetic glomerulosclerosis. For example, nonenzymatic glycations of type IV collagen and laminin reduce their ability activation. Further, Ang II augmented AGE-induced pericyte apoptosis, the earliest hallmark of diabetic retinopathy. Further, we have recently found that telmisartan blocks the Ang II-induced RAGE expression in ECs as well (Nakamura, Yamagishi, Nakamura et al. 2005). Telmisartan could decrease endothelial RAGE levels in patients with essential hypertension. Taken together, these observations provide the func- tional interaction between the AGE–RAGE system and the RAS in the pathogenesis of diabetic retinopathy, thus suggesting a novel bene cial aspect of telmisartan on the devastating disorder. We posit a table that presents the etiologies of diabetic retinopathy and its possible therapeutic agents (Table 21.2). ROLE OF AGES IN DIABETIC NEPHROPATHY Diabetic nephropathy is a leading cause of ESRD and accounts for disabilities and the high mortality rate in patients with diabetes (Krolewski, Warram, Valsania et al. 1991). Development of diabetic nephropathy is characterized by glomerular hyper ltration and thickening of glomerular basement membranes, fol- lowed by an expansion of extracellular matrix in mesangial areas and increased urinary albumin excretion rate (UAER). Diabetic nephropathy ultimately progresses to glomerular sclerosis associated with renal dysfunction (Sharma, Ziyadeh 1995). Further, it has recently been recognized that changes within tubulointerstitium, including proximal tubular cell atro- phy and tubulointerstitial  brosis, are also important in terms of renal prognosis in diabetic nephropathy (Ziyadeh, Goldfarb 1991; Lane, Steffes, Fioretto et al. 1993; Taft, Nolan, Yeung et al. 1994; Jones, Saunders, Qi et al. 1999; Gilbert, Cooper 1999). Such tubular changes have been reported to be the dominant lesion in about one-third of patients with type 2 diabetes (Fiorreto, Mauer, Brocco et al. 1996). It appears that both metabolic and hemodynamic factors interact to stimulate the expression of cytokines and growth factors in glomeruli and tubules from the diabetic kidney Table 21.2 Diabetic Retinopathy Etiology Cellular Pathway Treatment Regimen AGE–RAGE VEGF Pimagedine ROS ICAM-1 Amadorins Polyol pathway MCP-1 OPB-9195 PKC PAI-1 sRAGE RAS Angiopoietins PEDF Benfotiamine Telmisartan NOVEL CELLULAR PATHWAYS 530 malondialdehyde-lysine accumulate in the expanded mesangial matrix and thickened glomerular basement membranes of early diabetic nephropathy, and in nodular lesions of advanced disease, further suggesting the active role of AGEs for diabetic nephropathy (Suzuki, Miyata, Saotome et al. 1999). A number of studies have demonstrated that aminoguanidine decreased AGE accumulation and plasma protein trapping in the glomerular basement membrane (Matsumura, Yamagishi, Brownlee 2000). In streptozocin-induced diabetic rats, aminoguanidine treatment for 32 weeks dramatically reduced the level of albumin excretion and prevented the development of mesangial expansion (Soulis-Liparota Cooper, Papazoglou et al. 1991). Furthermore, aminoguanidine treatment was found to prevent albuminuria in diabetic hypertensive rats without affecting blood pressure (Edelstein, Brownlee 1992). Whether inhibition by aminoguanidine of inducible nitric oxide synthase (iNOS) could contribute to these renopro- tective effects remains to be elucidated. However, methylguanidine, which inhibits iNOS but not AGE formation, was reported not to retard the development of albuminuria in diabetic rats (Soulis, Cooper, Sastra et al. 1997). These observations suggest that the bene cial effects of aminoguanidine could be mediated predominantly by decreased AGE formation rather than by iNOS inhibition. A recent randomized, double-masked, placebo-controlled study (ACTION I trial) revealed that pimagedine R (aminoguanidine) reduced the decrease in glomerular  ltration rate and 24-hour total proteinuria in type 1 diabetic patients (Bolton, Cattran, Williams et al. 2004). Although the time for doubling of serum creatinine, a primary end point of this study, was not signi cantly improved by pimagedine R treatment (P = 0.099), the trial provided the  rst clinical proof of the concept that blockade of AGE formation could result in a signi cant attenua- tion of diabetic nephropathy. We have found that OPB-9195, a synthetic thiazoli- dine derivative and novel inhibitor of AGEs, prevented the progression of diabetic nephropathy by lowing serum concentrations of AGEs and their deposition of glomeruli in Otsuka–Long–Evans–Tokushima– Fatty rats, a type 2 diabetes mellitus model animal (Tsuchida, Makita, Yamagishi et al. 1999). OPB-9195 was also found to retard the progression of diabetic nephropathy by blocking type IV collagen production and suppressing overproduction of two growth factors, TGF-β and VEGF. Recently, Degenhardt and Baynes et al. (Degen- hardt, Alderson, Arrington et al. 2002) reported that pyridoxamine inhibited the progression of renal disease and decreases hyperlipidemia and apparent redox imbalances in diabetic rats. Pyridoxamine and aminoguanidine had similar effects on parameters to interact with negatively charged proteoglycans, increasing vascular permeability to albumin (Silbiger, Crowley, Shan et al. 1993). Furthermore, AGE formation on various types of matrix proteins impairs their degradation by matrix metalloproteinases, contribut- ing to basement membrane thickening and mesangial expansion, hallmarks of diabetic nephropathy (Brownlee 1993; Mott, Khalifah, Nagase et al. 1997). AGEs formed on the matrix components can trap and covalently cross-link with the extravasated plasma proteins such as lipoproteins, thereby exacerbating diabetic glomerulosclerosis (Brownlee 1993). AGEs stimulate insulin-like growth factor-I, -II, PDGF and TGF-β in mesangial cells, which in turn mediate production of type IV collagen, laminin, and  bronectin (Matsumura, Yamagishi, Brownlee 2000; Yamagishi, Takeuchi, Makita 2001). AGEs induce TGF-β overexpression in both podocytes and proximal tubular cells as well (Wendt TM, Tanji N, Guo J, et al. 2003; Yamagishi, Inagaki, Okamoto et al. 2003). Recently, Ziyadeh et al. (2000) reported that long- term treatment of type 2 diabetic model mice with blocking antibodies against TGF-β suppressed excess matrix gene expression, glomerulosclerosis, and prevented the development of renal insuf ciency. These observations suggest that AGE-induced TGF-β expression plays an important role in the pathogenesis of glomerulosclerosis and tubulointerstitial  brosis in diabetic nephropathy (Raj, Choudhury, Welbourne et al. 2000; Yamagishi, Koga, Inagaki et al. 2002). In vivo, the administration of AGE-albumin to normal healthy mice for 4 weeks has been found to induce glomerular hypertrophy with overexpression of type IV collagen, laminin B1, and TGF-β genes (Yang, Vlassara, Peten et al. 1994). Furthermore, chronic infusion of AGE-albumin to otherwise healthy rats leads to focal glomerulosclerosis, mesangial expansion, and albuminuria (Vlassara H, Striker LJ, Teichberg et al. 1994). Recently, RAGE- overexpressing diabetic mice have been found to show progressive glomerulosclerosis with renal dysfunction, compared with diabetic littermates lacking the RAGE transgene (Yamamoto, Kato, Doi et al. 2001). Further, diabetic homozygous RAGE null mice failed to develop signi cantly increased mesangial matrix expansion or thickening of the glomerular basement membrane (Wendt, Tanji, Guo et al. 2003). Taken together, these  ndings suggest that the activation of AGE–RAGE axis contributes to expression of VEGF and enhanced attraction/activation of in ammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-β production; processes that converge to cause albuminuria and glomerulosclerosis. AGEs including glycoxidation or lipoxidation products such as N ε -(carboxymethyl)lysine, pentosidine, Chapter 21: Diabetic Vascular Complications 531 ROLE OF AGES IN CVD Atherosclerotic arterial disease may be manifested clinically as CVD. Deaths from CVD predominate in patients with diabetes of over 30 years’ duration and in those diagnosed after 40 years of age. CVD is responsible for about 70% of all causes of death in patients with type 2 diabetes (Laakso 1999). In Framingham study, the incidence of CVD was 2 to 4 times greater in diabetic patients than in general polulation (Haffner, Lehto, Ronnemaa et al. 1998). Conventional risk factors, including hyperlipidemia, hypertension, smoking, obesity, lack of exercise, and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and nondiabetic subjects (Laakso 1999). The levels of these factors in diabetic patients were certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in diabetic population (Standl, Balletshofer, Dahl et al. 1996). Therefore, speci c diabetes-related risk factors should be involved in the excess risk in diabetic patients. A variety of molecular mechanisms underlying the actions of AGEs and their contribution to diabetic macrovascular complications have been proposed (Stitt, Bucala, Vlassara 1997; Bierhaus, Hofmann, Ziegler et al. 1998; Schmidt, Stern 2000; Vlassara, Palace 2002; Wendt, Bucciarelli, Qu et al. 2002). AGEs formed on the extracellular matrix results in decreased elasticity of vasculatures, and quench nitric oxide, which could mediate defective endothelium- dependent vasodilatation in diabetes (Bucala, Tracey, Cerami 1991). AGE modi cation of low-density lipoprotein (LDL) exhibits impaired plasma clearance and contributes signi cantly to increased LDL in vivo, thus being involved in atherosclerosis (Bucala, Mitchell, Arnold et al. 1995). Binding of AGEs to RAGE results in generation of intracellular ROS generation and subsequent activation of the redox- sensitive transcription factor NF-κB in vascular wall cells, which promotes the expression of a variety of atherosclerosis-related genes, including ICAM-1, vascular cell adhesion molecule-1, MCP-1, PAI-1, tissue factor, VEGF, and RAGE (Stitt, Bucala, Vlassara 1997; Bierhaus, Hofmann, Ziegler et al. 1998; Schmidt, Stern 2000; Tanaka, Yonekura, Yamagishi et al. 2000; Vlassara, Palace 2002; Wendt, Bucciarelli, Qu et al. 2002). AGEs have the ability to induce osteoblas- tic differentiation of microvascular pericytes, which would contribute to the development of vascular cal- ci cation in accelerated atherosclerosis in diabetes as well (Yamagishi, Fujimori, Yonekura et al. 1999). The interaction of the RAS and AGEs in the development of diabetic macrovascular complications has also been proposed. AGE–RAGE interaction augments measured, supporting a mechanism of action involv- ing AGE inhibition (Degenhardt, Alderson, Arrington et al. 2002). Although the results of AGE inhibitors in animal models of diabetic nephropathy are promising, effectiveness of these AGE inhibitors must be con rmed by multicenter, randomized, double-blind clinical studies. Cross Talk between the AGE–RAGE Axis and the RAS in Diabetic Nephropathy Recent experiments have focused on the interaction of the AGE–RAGE axis and the RAS thought to be critical to the development of diabetic nephropathy. Indeed, angiotensin converting enzyme inhibition reduces the accumulation of renal and serum AGEs, probably via effects on oxidative pathways (Forbes, Cooper, Thallas et al. 2002). Long-term treatment with Ang II receptor 1 antagonist may exert salu- tary effects on AGEs levels in the rat remnant kidney model, probably due to improved renal function (Sebekova, Schinzel, Munch et al. 1999). Ramipril administration has been recently shown to result in a mild decline of  uorescent non-carboxymethyllysine- AGEs and malondialdehyde concentrations in nondiabetic nephropathy patients (Sebekova, Gazdikova, Syrova et al. 2003). Further, we have recently found that the AGE–RAGE-mediated ROS generation activates TGF-β-Smad signaling and subsequently induces mesangial cell hypertrophy and  bronectin synthesis by autocrine production of Ang II (Fukami, Ueda, Yamagishi et al. 2004). In addition, AGEs induce mitogenesis and collagen production in renal interstitial  broblasts as well via Ang II-connective tissue growth factor pathway (Lee, Guh, Chen et al. 2005). Moreover, olmesartan medoxomil, an Ang II type 1 receptor blocker, protects against glomerulosclerosis and renal tubular injury in AGE-injected rats, thus further supporting the concept that AGEs could induce renal damage in diabetes partly via the activation of RAS (Yamagishi, Takeuchi, Inoue et al. 2005). We posit a table that presents the etiologies of diabetic nephropathy and its possible therapeutic agents (Table 21.3). Table 21.3 Diabetic Nephropathy Etiology Cellular Pathway Treatment Regimen AGE–RAGE VEGF Pimagedine ROS MCP-1 Pyridoxamine PKC TGF-β OPB-9195 RAS Smad Olmesartan Hyper ltration NOVEL CELLULAR PATHWAYS 532  vefold lower AGE content signi cantly decreased serum levels of AGEs, soluble form of VCAM-1 and C-reactive protein (CRP), compared to equivalent regular diets (Vlassara, Cai, Crandall et al. 2002). AGE-poor diets also reduced peripheral mononu- clear cell tumor necrosis factor-α (TNF-α) expression at both mRNA and protein levels (Vlassara, Cai, Crandall et al. 2002). Further, LDL pooled from diabetic patients on a standard diet for 6 weeks (high AGE-LDL) was more glycated and oxidized than that from diabetic patients on an AGE-poor diet (low AGE-LDL) (Cai, He, Zhu et al. 2004). High AGE-LDL signi cantly induced soluble form of VCAM-1 expression in human umbilical vein ECs via redox-sensitive MAPK activation, compared to native LDL or low AGE-LDL (Cai, He, Zhu et al. 2004). In addition, AGE pronyl-glycine, a food-derived AGE, was reported to elicit in ammatory response to cellular proliferation in an intestinal cell line, Caco-2, through the RAGE- mediated MAPK activation (Zill, Bek, Hofmann et al. 2003). These observations suggest the causal link between dietary intake of AGEs and proin ammation and vascular injury, thus providing the clinical relevance of dietary AGE restriction in the prevention of accelerated atherosclerosis in diabetes. We have very recently found that PAI-1 and  brinogen levels are positively associated with serum AGE levels in nondiabetic general population. Food-derived AGEs may also be associated with thrombogenic tendency in nondiabetic subjects (Enomoto, Adachi, Yamagishi et al. 2006). CONCLUSION In the DCCT-EDIC, the reduction in the risk of progressive diabetic micro- and macroangipathies resulting from intensive therapy in patients with type 1 diabetes persisted for at least several years, despite increasing hyperglycemia (DCCT-EDIC Research Group 2000; Writing Team for DCCT-EDIC Research Group 2003; Nathan, Lachin, Cleary et al. 2003; Nathan, Cleary, Backlund et al. 2005). These clinical studies strongly suggest that so-called hyperglycemic memory is involved in the pathogenesis of diabetic vascular complications, AGE hypothesis seems to be most compatible with this theory. Moreover, large clinical investigations will be needed to clar- ify whether the inhibition of AGE formation or the blockade of their downstream signaling could prevent the development and progression of vascular complications in diabetes. Until the speci c remedy that targets diabetic vascular complications are devel- oped, multifactorial intensi ed intervention will be a promising therapeutic strategy for the prevention of these devastating disorders. Ang II-induced smooth muscle cell proliferation and activation, thus being involved in accelerated atherosclerosis in diabetes (Shaw, Schmidt, Banes et al. 2003). AGEs have been actually detected within atherosclerotic lesions in both extra- and intracellular locations (Nakamura, Horii, Nishino et al. 1993; Niwa, Katsuzaki, Miyazaki et al. 1997; Sima, Popov, Starodub et al. 1997). In animal models, Park et al. (1998) has demonstrated that diabetic apolipoprotein E (apoE) null animals receiving soluble RAGE (sRAGE) display a dose-dependent suppression of accelerated atherosclerosis in these mice. Lesions that formed in animals receiving sRAGE appeared largely arrested at the fatty streak stage; the number of complex atherosclerotic lesions was strikingly reduced in diabetic apoE null mice. The tissue and plasma AGE burden was suppressed in diabetic apoE null mice receiving sRAGE, suggesting that the AGE–RAGE-induced oxidative stress generation might participate in AGEs formation themselves. Treatment with sRAGE did not affect the levels of established risk factors in these mice. These observations suggest the active involve- ment of AGE–RAGE interaction in the pathogenesis in accelerated atherosclerosis in diabetes. The same group has recently reported that the AGE–RAGE system contributes to the atherosclerotic lesion progression as well, and RAGE blockade stabilizes the lesions in these mice (Bucciarelli, Wendt, Qu et al. 2002). Another study shows a correlation between AGE levels and the degree of atheroma in cholesterol-fed rabbits, and aminoguanidine has an antiatherogenic effect in these rabbits by inhibiting AGEs formation (Panagiotopoulos, O’Brien, Bucala et al. 1998). In humans, RAGE overexpression is associated with enhanced in ammatory reaction and cyclooxygenase-2 and prostaglandin E synthase-1 expression in diabetic plaque macrophages, and this effect may contribute to plague destabilization by inducing culprit metalloproteinase expression (Cipollone, Iezzi, Fazia et al. 2003). Recently, food-derived AGEs are reported to induce oxidative stress and promote in ammatory signals (Cai, Gao, Zhu et al. 2002). Dietary glycotoxins promote diabetic atherosclerosis in apoE-de cient mice (Lin, Reis, Dore et al. 2002; Lin, Choudhury, Cai et al. 2003). 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Nicotinamide Pl 3-K IKK p Akt IκB Dishevelled p FOXO3a GSK-3β NF-κB p Mito ∆Ψm ↓ β-Catenin p-β-Catenin p-FOXO3a 1 4-3 -3 IAPs Bcl-xL p-GSK-3β Cytochrome c and caspase release Lef/Tcf Gene transcription Apoptosis PS exposure DNA fragmentation Activation of microglia Phagocytosis Figure 22.1 Erythropoietin (EPO), nicotinamide, and Wnt use diverse as well as common pathways to foster cellular longevity EPO... by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice Proc Natl Acad Sci U S A 97:8015–8020 Chapter 22 REDUCING OXIDATIVE STRESS AND ENHANCING NEUROVASCULAR LONGEVITY DURING DIABETES MELLITUS Kenneth Maiese, Zhao Zhong Chong, and Faqi Li ABSTRACT Our book Neurovascular Medicine: Pursuing Cellular Longevity for Healthy Aging provides a unique perspective from... EPO and the EPO receptor (EPOR) can increase cellular longevity through protein kinase B (Akt), the forkhead transcription factor family member FOXO3a, glycogen synthase kinase-3β (GSK-3β), nuclear factor-κB (NF-κB), and Bcl-xL Similar to EPO, nicotinamide modulates the activity of FOXO3a through phosphorylation (p) along with 14– 3-3 protein and can maintain cellular integrity and prevent inﬂammatory... kinase (GSK-3β) through phosphorylation (p) The suppressed GSK-3β along with other Wnt signaling complexes prevents phosphorylation (p) of β-catenin and leads to the accumulation of β-catenin β-catenin enters into cellular nucleus and contributes to the formation of lymphocyte enhancer factor/T cell factor (Lef/Tcf) and the β-catenin complex that leads to gene transcription, resulting in cellular proliferation,... de Schans, van den Borne, Strzelecka et al 2007) 551 Chapter 22: Oxidative Stress and Neurovascular Longevity in DM Wnt signaling can prevent cell injury through β-catenin/Tcf transcription-mediated pathways (Chen, Guttridge, You et al 2001b) and against c-myc-induced apoptosis through cyclooxygenase- 2- and Wnt-induced secreted protein (You, Saims, Chen et al 2002) However, more recent work has linked... vascular, and immune-mediated disease processes to translate basic cellular mechanisms into viable therapeutic measures Yet, as with any form of published literature, the work presented is not all encompassing and intends to not only highlight and explore new avenues to extend cell longevity for healthy aging but also outline the potential concerns and limitations of novel treatment approaches for patients... 2007) Chapter 22: Oxidative Stress and Neurovascular Longevity in DM INNOVATIVE DIRECTIONS FOR NEUROVASCULAR PROTECTION DURING DM Possible pathways that may decrease neuronal and vascular longevity during DM are broad in scope and involve multiple precipitating factors Yet, oxidative stress-induced cellular signaling is believed to be a significant factor responsible for cell injury that is initially set... Insulin-stimulated insulin receptor substrate2-associated phosphatidylinositol 3-kinase activity is enhanced in human skeletal muscle after exercise Metabolism 55 :104 6 105 2 Hu Y, Wang Y et al 1996 Effects of nicotinamide on prevention and treatment of streptozotocin-induced diabetes mellitus in rats Chin Med J (Engl) 109 :819–822 Ieraci A, Herrera DG 2006 Nicotinamide protects against ethanol-induced... 2003 Nerve growth factor protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a phosphatidylinositol 3-kinase-dependent manner J Biol Chem 278:13898–13904 Salinas PC 1999 Wnt factors in axonal remodelling and synaptogenesis Biochem Soc Symp 65 :101 109 Sanz O, Acarin L, Gonzalez B, Castellano B 2002 NF-kappaB and IkappaBalpha expression following... 2006c) (Table 22.2) A Precursor for the Coenzyme 𝛃-Nicotinamide Adenine Dinucleotide As the amide form of niacin or vitamin B3, nicotinamide plays a critical role in cellular metabolism and can offer significant neuronal and vascular cell protection during a wide range of disorders that include DM Nicotinamide is the precursor for the coenzyme β-NAD+ and is essential for the synthesis of nicotinamide . ENHANCING NEUROVASCULAR LONGEVITY DURING DIABETES MELLITUS Kenneth Maiese, Zhao Zhong Chong, and Faqi Li ABSTRACT Our book Neurovascular Medicine: Pursuing Cellular Longevity for Healthy Aging. release IAPs 1 4-3 -3 p-FOXO3a FOXO3a Akt Pl 3-K Nicotinamide LRP5/6 Frizzled EPO Wnt EPOR Dishevelled p-GSK-3βGSK-3β β-Catenin Lef/Tcf Gene transcription PS exposure Activation of microglia Phagocytosis p-β-Catenin Mito. disease. Kidney Int Suppl. 63:S107–S 110. Antonelli-Orlidge A, Saunders KB, Smith SR, D’Amore PA. 1989. An active form of transforming growth factor-β was produced by co-cultures of ECs and pericytes.

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