Advanced Glycation End-Products Induce Apoptosis in Pancreatic Islet Endothelial Cells via NF-κB-Activated Cyclooxygenase-2/Prostaglandin E2 Up-Regulation

Abstract

Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs) resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF)-κB-p65 phosphorylation and cyclooxygenase (COX)-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER) stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor) to inhibit prostaglandin E2 (PGE2) production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE) protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.

Intake of high fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent coronary heart disease, in U.S. adults, ages 45–59 y

“…According to the "fructositis" hypothesis, underlying fructose malabsorption and unabsorbed EFF may contribute to the intestinal in situ formation of AGE (enFruAGE). GI generated AGE may be an overlooked source of immunogens that travel to other tissues and promote inflammation by binding the pro-inflammatory receptor of advanced glycation end-products (RAGE) [23], known to be concentrated in the lungs, heart, connective tissues, lymph nodes [57] and, as recently discovered, the pancreas, in the presence of AGE [58,59]. Coronary heart disease (CHD) is defined as self-reported current or history of doctor diagnosed CHD and/ or angina pectoris [36].…”

“…In 2003-2006 [the NHANES study period], high fructose corn syrup was the main sweetener in US soft drinks [31]. Odds ratios were considered statistically significant if the 95% confidence intervals did not include 1 and p values were <0.05, as indicated by italics accumulate in the pancreas and contribute to pancreatitis and impaired ß-cell function; [58,59] AGE are elevated in connective tissues including the synovium, sub-lining, and cartilage of autoimmune arthritis sufferers [71][72][73][74][75]; and the receptor of advanced glycation end-products (RAGE) is a key mediator of asthma [76].…”

Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes

“…The apoptosis of cardiomyocytes can be induced by multiple factors, including oxidative stress [5], inflammation [6], endoplasmic reticulum (ER) stress [7] and advanced glycation end products (AGEs) [8]. Continuous high glucose in DM induces oxidative stress and excessive ROS production.…”

“…Cardiomyocyte apoptosis is an important pathological alteration during DCM [3] and is thought to lead to persistent loss of effective myocardial contractile units [4], promote cardiac remodeling and eventually lead to cardiac failure. The apoptosis of cardiomyocytes can be induced by multiple factors, including oxidative stress [5], inflammation [6], endoplasmic reticulum (ER) stress [7] and advanced glycation end products (AGEs) [8]. Continuous high glucose in DM induces oxidative stress and excessive ROS production.…”

iRAGE as a novel carboxymethylated peptide that prevents advanced glycation end product-induced apoptosis and endoplasmic reticulum stress in vascular smooth muscle cells

“…Notably, RAGE contribution to cell apoptosis was demonstrated in diabetic retinopathy 12,13 (retinal pericytes), keratopathy 14 (corneal epithelial cells), nephropathy 15,16 (podocytes and mesangial cells), deficits in wound healing 17 (fibroblasts), periodontal disease [18][19][20] (osteoblasts and fibroblasts), osteopenia 21 (bone marrow stromal cells) and in microvascular complications [22][23][24] (endothelial cells). Although VSMC apoptosis in diabetes is welldocumented 25,26 , the contribution of RAGE to this phenomenon remains unclear.…”