Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

Ward, Micheal; Fotheringham, Amelia K.; Cooper, Mark E.; Forbes, Josephine M.

doi:10.1016/j.coph.2013.06.009

Cited by 49 publications

(23 citation statements)

References 60 publications

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“…However, excessive ROS production under pathological conditions such as ischemia and mitochondrial membrane depolarization is detrimental to cellular function [43]. In our study, AK2 -knockdown treatment specifically enhanced ROS production in ATRA-induced neutrophil differentiated HL-60 cells (Figure 5C).…”

Section: Resultssupporting

confidence: 47%

Differential Expression of Adenine Nucleotide Converting Enzymes in Mitochondrial Intermembrane Space: A Potential Role of Adenylate Kinase Isozyme 2 in Neutrophil Differentiation

et al. 2014

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Adenine nucleotide dynamics in the mitochondrial intermembrane space (IMS) play a key role in oxidative phosphorylation. In a previous study, Drosophila adenylate kinase isozyme 2 (Dak2) knockout was reported to cause developmental lethality at the larval stage in Drosophila melanogaster. In addition, two other studies reported that AK2 is a responsible gene for reticular dysgenesis (RD), a human disease that is characterized by severe combined immunodeficiency and deafness. Therefore, mitochondrial AK2 may play an important role in hematopoietic differentiation and ontogenesis. Three additional adenine nucleotide metabolizing enzymes, including mitochondrial creatine kinases (CKMT1 and CKMT2) and nucleoside diphosphate kinase isoform D (NDPK-D), have been found in IMS. Although these kinases generate ADP for ATP synthesis, their involvement in RD remains unclear and still an open question. In this study, mRNA and protein expressions of these mitochondrial kinases were firstly examined in mouse ES cells, day 8 embryos, and 7-week-old adult mice. It was found that their expressions are spatiotemporally regulated, and Ak2 is exclusively expressed in bone marrow, which is a major hematopoietic tissue in adults. In subsequent experiments, we identified increased expression of both AK2 and CKMT1 during macrophage differentiation and exclusive production of AK2 during neutrophil differentiation using HL-60 cells as an in vitro model of hematopoietic differentiation. Furthermore, AK2 knockdown specifically inhibited neutrophil differentiation without affecting macrophage differentiation. These data suggest that AK2 is indispensable for neutrophil differentiation and indicate a possible causative link between AK2 deficiency and neutropenia in RD.

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Section: Resultssupporting

confidence: 47%

Differential Expression of Adenine Nucleotide Converting Enzymes in Mitochondrial Intermembrane Space: A Potential Role of Adenylate Kinase Isozyme 2 in Neutrophil Differentiation

et al. 2014

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“…These data suggest that reducing the amount of AGEs in the diet could be a useful strategy for improving the management of diabetic complications. This concept was confirmed in studies showing that ingestion of foods with high AGE levels was a significant determinant of insulin resistance, increased inflammation, and reduced key antioxidant defenses, including NADdependent protein deacetylase surtuin-1 (SIRT1), advanced glycation end product receptor 1 (AGER1), and adiponectin in T2DM (11)(12)(13).…”

Section: Introductionmentioning

confidence: 81%

Effects of Sevelamer Carbonate on Advanced Glycation End Products and Antioxidant/Pro-Oxidant Status in Patients with Diabetic Kidney Disease

Yubero‐Serrano

Woodward

Poretsky³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives The primary goals were to re-examine whether sevelamer carbonate (SC) reduces advanced glycation end products (AGEs) (methylglyoxal and carboxymethyllysine [CML]), increases antioxidant defenses, reduces pro-oxidants, and improves hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Secondary goals examined albuminuria, age, race, sex, and metformin prescription.Design, setting, participants, & measurements This two-center, randomized, intention-to-treat, open-label study evaluated 117 patients with T2DM (HbA1c .6.5%) and stages 2-4 DKD (urinary albumin/creatinine ratio $200 mg/g) treated with SC (1600 mg) or calcium carbonate (1200 mg), three times a day, without changing medications or diet. Statistical analyses used linear mixed models adjusted for randomization levels. Preselected subgroup analyses of sex, race, age, and metformin were conducted.Results SC lowered serum methylglyoxal (95% confidence interval [CI], 20.72 to 20.29; P,0.001), serum CML (95% CI, 25.08 to 21.35; P#0.001), and intracellular CML (95% CI, 21.63 to 20.28; P=0.01). SC increased anti-inflammatory defenses, including nuclear factor like-2 (95% CI, 0.58 to 1.29; P=0.001), AGE receptor 1 (95% CI, 0.23 to 0.96; P=0.001), NAD-dependent deacetylase sirtuin-1 (95% CI, 0.20 to 0.86; P=0.002), and estrogen receptor a (95% CI, 1.38 to 2.73; P #0.001). SC also decreased proinflammatory factors such as TNF receptor 1 (95% CI, 21.56 to 20.72; P#0.001) and the receptor for AGEs (95% CI, 20.58 to 1.53; P#0.001). There were no differences in HbA1c, GFR, or albuminuria in the overall group. Subanalyses showed that SC lowered HbA1c in women (95% CI, 21.71 to 20.27; P=0.01, interaction P=0.002), and reduced albuminuria in those aged ,65 years (95% CI, 21.15 to 20.07; P=0.03, interaction P=0.02) and non-Caucasians (95% CI, 21.11 to 20.22; P=0.003, interaction P#0.001), whereas albuminuria increased after SC and calcium carbonate in Caucasians.Conclusions SC reduced circulating and cellular AGEs, increased antioxidants, and decreased pro-oxidants, but did not change HbA1c or the albumin/creatinine ratio overall in patients with T2DM and DKD. Because subanalyses revealed that SC may reduce HbA1c and albuminuria in some patients with T2DM with DKD, further studies may be warranted.

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“…Oxidative stress is induced by multiple pathways in diabetes. Hyperglycaemia causes excessive ROS synthesis by direct autoxidation during the formation of AGEs and by inducing mitochondrial dysfunction [41]. Experimental studies showed that AGEs can further increase ROS generation through AGE receptor (RAGE) by stimulating NADPH oxidase activity [42] and that AGE-induced oxidative stress is attenuated by NADPH oxidase inhibitor in human endothelial cells [43].…”

Section: Discussionmentioning

confidence: 99%

BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy

Yiu

et al. 2014

Clinical Science

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Bone morphogenetic protein 7 (BMP7) has been reported to confer renoprotective effects in acute and chronic kidney disease models, but its potential role in Type 2 diabetic nephropathy remains unknown. In cultured human proximal tubular epithelial cells (PTECs), exposure to advanced glycation end-products (AGEs) induced overexpression of intercellular adhesion molecule 1 (ICAM1), monocyte chemoattractant protein 1 (MCP1), interleukin 8 (IL-8) and interleukin 6 (IL-6), involving activation of p44/42 and p38 mitogen-activated protein kinase (MAPK) signalling. BMP7 dose-dependently attenuated AGE-induced up-regulation of ICAM1, MCP1, IL-8 and IL-6 at both mRNA and protein levels. Moreover, BMP7 suppressed AGE-induced p38 and p44/42 MAPK phosphorylation and reactive oxygen species production in PTECs. Compared with vehicle control, uninephrectomized db/db mice treated with BMP7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3549±816.2 μg/mg compared with 8612±2037 μg/mg, P=0.036), blood urea nitrogen (33.26±1.09 mg/dl compared with 37.49±0.89 mg/dl, P=0.006), and renal cortical expression of ICAM1 and MCP1 at both gene and protein levels. In addition, BMP7-treated animals had significantly less severe tubular damage, interstitial inflammatory cell infiltration, renal cortical p38 and p44/42 phosphorylation and lipid peroxidation. Our results demonstrate that BMP7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple inflammatory signalling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule in diabetic nephropathy warrants further investigation.

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Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease

Cited by 49 publications

References 60 publications

Differential Expression of Adenine Nucleotide Converting Enzymes in Mitochondrial Intermembrane Space: A Potential Role of Adenylate Kinase Isozyme 2 in Neutrophil Differentiation

Differential Expression of Adenine Nucleotide Converting Enzymes in Mitochondrial Intermembrane Space: A Potential Role of Adenylate Kinase Isozyme 2 in Neutrophil Differentiation

Effects of Sevelamer Carbonate on Advanced Glycation End Products and Antioxidant/Pro-Oxidant Status in Patients with Diabetic Kidney Disease

BMP7 reduces inflammation and oxidative stress in diabetic tubulopathy

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