Advanced Glycation End Products-Induced Apoptosis and Overexpression of Vascular Endothelial Growth Factor in Bovine Retinal Pericytes

Yamagishi, Sho‐ichi; Amano, Shoichi; Inagaki, Yoshishige; Okamoto, Tamami; Koga, Kohachiro; Sasaki, Nobuyuki; Yamamoto, Hiroshi; Takeuchi, Masayoshi; Makita, Zenji

doi:10.1006/bbrc.2001.6312

Cited by 196 publications

(148 citation statements)

References 32 publications

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“…In order to test this hypothesis we exposed undifferentiated and differentiated SH-SY5Y human neuroblastoma cells, which are nNOS-negative and positive respectively, to exogenous HSA-AGEs. HSA-AGEs alone produced caspase-3-dependent apoptotic cell death, in accordance with previous studies [28,29]. HSA-AGEs-induced apoptosis was significantly increased in the nNOS-positive cells; this could be prevented if the cells were treated with an inhibitor of NOS, suggesting a synergistic action of AGEs and NO in inducing apoptosis.…”

Section: Discussionsupporting

confidence: 91%

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

et al. 2004

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Aims/hypothesis. We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression. Methods. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose. Results. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase. Conclusions/interpretation. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes. [Diabetologia (2004) 47: 331-339]

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Section: Discussionsupporting

confidence: 91%

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

et al. 2004

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“…Soluble AGE are known to induce apoptotic death in retinal pericytes [11,44], a response that may be associated with increased oxidative stress [45] and inhibited by treatment with antioxidants [44,46] or protective growth factors [47]. There may also be an association with AGE-receptor modulation of this response [46].…”

Section: Discussionmentioning

confidence: 99%

“…Hyperglycaemia-mediated pericyte dysfunction and, ultimately, premature pericyte death are a major pathogenic consequence of diabetic retinopathy [5], although the precise nature of the biochemical insult and of the subsequent death response remains illdefined. A range of in vitro and in vivo studies have demonstrated that retinal pericytes enter an apoptosisrelated death pathway after long-term diabetes in humans [6,7], during experimental diabetes or hyperhexosaemia [8,9], and after exposure to biochemical insults in culture [10,11].…”

Section: Introductionmentioning

confidence: 99%

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor

et al. 2004

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Aims/hypothesis. Premature death of retinal pericytes is a pathophysiological hallmark of diabetic retinopathy. Among the mechanisms proposed for pericyte death is exposure to AGE, which accumulate during diabetes. The current study used an in vitro model, whereby retinal pericytes were exposed to AGE-modified substrate and the mechanisms underlying pericyte death explored. Methods. Pericytes were isolated from bovine retinal capillaries and propagated on AGE-modified basement membrane (BM) extract or non-modified native BM. The extent of AGE modification was analysed. Proliferative responses of retinal pericytes propagated on AGE-modified BM were investigated using a 5-bromo-2-deoxy-uridine-based assay. The effect of extrinsically added platelet-derived growth factor (PDGF) isoforms on these proliferative responses was also analysed alongside mRNA expression of the PDGF receptors. Apoptotic death of retinal pericytes grown on AGE-modified BM was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling labelling, mitochondrial membrane depolarisation and by morphological assessment. We also measured both the ability of PDGF to reverse Akt dephosphorylation that was mediated by AGE-modified BM, and increased pericyte apoptosis. Results. Retinal pericytes exposed to AGE-modified BM showed reduced proliferative responses in comparison to controls (p<0.05-0.01), although this effect was reversed at low-AGE modifications. PDGF mRNA levels were differentially altered by exposure to low and high AGE levels, and AGE-modified BM caused significantly increased apoptosis in retinal pericytes. Pre-treatment of AGE-modified BM with PDGF-AA and -BB reversed the apoptosis (p<0.05-0.001) and restored Akt phosphorylation in retinal pericytes. Conclusions/interpretation. Evidence suggests that substrate-derived AGE such as those that occur during diabetes could have a major influence on retinal pericyte survival. During diabetic retinopathy, AGE modification of vascular BM may reduce bioavailability of pro-survival factors for retinal pericytes.

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“…43,44 Such actions lead to an increased microthrombosis, capillary blockage, retinal ischemia and the activation of endothelial cells, responsible for important shortcomings involving mesangial cells and stimulating glomerular fibrosis. 45,46 It has been suggested that, among black population, microvascular damage is due to a different genetic predisposition that stimulates the accumulation of AGEs with all the after-effects. 45,46 The strong association between diabetes mellitus and hypertension among the African population, compared to the white population, worsens dramatically microvascular damage.…”

Section: Diabetes Mellitusmentioning

confidence: 99%

“…45,46 It has been suggested that, among black population, microvascular damage is due to a different genetic predisposition that stimulates the accumulation of AGEs with all the after-effects. 45,46 The strong association between diabetes mellitus and hypertension among the African population, compared to the white population, worsens dramatically microvascular damage. 47,48 …”

Section: Diabetes Mellitusmentioning

confidence: 99%

Cardiovascular risk factors in sub-Saharan Africa: a review

Monti¹,

Ruggieri²,

Vincentelli

et al. 2015

Ital J Med

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Ischemic heart disease is increasing dramatically in the Sub-Saharan Africa (SSA), despite an increasing prevalence of risk factors, and some characteristics of the African people that make the African population subject to the effects of major cardiovascular risk factors. The pace and direction of economic development, rates of urbanization, the changes in life expectancy, associated with different pathophysiological factors are causing an increased rate of atherosclerotic disease in these countries. The prevalence of ischemic heart disease in SSA has shown a significant rise in the next two following decades due to the rising prevalence of risk factors, especially hypertension, diabetes, overweight and obesity, physical inactivity, tobacco use and the dyslipidemia, mainly due to an increase in urbanization. Moreover, thanks to new knowledge, it has been pointed out the difference of individual risk factors in the African population and other populations due to genetic differences. It is estimated that age-standardized approach for ischemic heart disease mortality rates will rise by 27% in African men and 25% in women by 2015 and by 70 and 74%, respectively by 2030. More research is needed in Africa to provide evidence for cardiovascular prevention and treatment to mitigate the oncoming epidemic. Health interventions are needed for preventing or reducing the morbidity/mortality and should be addressed to both children and adults, including score of the risk stratification modified, starting early and aggressive therapy, if necessary.

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Advanced Glycation End Products-Induced Apoptosis and Overexpression of Vascular Endothelial Growth Factor in Bovine Retinal Pericytes

Cited by 196 publications

References 32 publications

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor

Cardiovascular risk factors in sub-Saharan Africa: a review

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