4-hydroxy-2-nonenal and Diabetes-Mellitus

A major pathophysiological mechanism behind the development of diabetic heart diseases is oxidative stress mediated by toxic reactive aldehydes such as 4-hydroxynonenal (4HNE). Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial enzyme that has been found to detoxify these deleterious aldehydes and thereby mitigate cardiac damage. Furthermore, its protective role in cellular signaling reverses aberrations caused by hyperglycemia, thereby protecting cardiac function. This chapter assesses the role of ALDH2 in diabetic heart diseases by examining preclinical studies where ALDH2 activity is perturbed in both decreased and increased directions. In doing so, issues in improving ALDH2 activity in select human populations are elucidated, and further research directions are discussed.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Diabetes Mellitus; Heart Diseases; Humans; Oxidative Stress

Mitochondrial lipids are essential for maintaining the integrity of mitochondrial membranes and the proper functions of mitochondria. As the "powerhouse" of a cell, mitochondria are also the major cellular source of reactive oxygen species (ROS). Oxidative stress occurs when the antioxidant system is overwhelmed by overproduction of ROS. Polyunsaturated fatty acids in mitochondrial membranes are primary targets for ROS attack, which may lead to lipid peroxidation (LPO) and generation of reactive lipids, such as 4-hydroxynonenal. When mitochondrial lipids are oxidized, the integrity and function of mitochondria may be compromised and this may eventually lead to mitochondrial dysfunction, which has been associated with many human diseases including cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases. How mitochondrial lipids are oxidized and the underlying molecular mechanisms and pathophysiological consequences associated with mitochondrial LPO remain poorly defined. Oxidation of the mitochondria-specific phospholipid cardiolipin and generation of bioactive lipids through mitochondrial LPO has been increasingly recognized as an important event orchestrating apoptosis, metabolic reprogramming of energy production, mitophagy, and immune responses. In this review, we focus on the current understanding of how mitochondrial LPO and generation of bioactive lipid mediators in mitochondria are involved in the modulation of mitochondrial functions in the context of relevant human diseases associated with oxidative stress.

Topics: Aldehydes; Animals; Apoptosis; Cardiolipins; Cardiovascular Diseases; Diabetes Mellitus; Fatty Acids, Unsaturated; Humans; Lipid Peroxidation; Mitochondria; Mitochondrial Membranes; Mitophagy; Neoplasms; Neurodegenerative Diseases; Oxidative Stress; Reactive Oxygen Species

Activated peroxisome proliferator-activated receptor-δ (PPARδ) induces the expression of genes encoding enzymes that metabolize fatty acids and carbohydrate. Attempts to identify cellular activators of PPARδ produced large lists of various fatty acids and their metabolic derivatives; however, there is no consensus on specific and selective binding interactions of natural ligands with PPARδ. Most models on binding interactions within the ligand binding domain (LBD) of PPARδ have been derived from analyses of PPARδ-LBD crystals formed with synthetic low molecular weight ligands. Nonetheless, crystals of the whole receptor with natural ligands or of its heterodimer with its cognate retinoid X receptor (RXR) are not yet available for analysis. We have found that 4-hydroxyalkenals, non-enzymatic peroxidation products of polyunsaturated fatty acids (PUFA), namely, 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) and 4-hydroxy-2E-nonenal (4-HNE), activate PPARδ in vascular endothelial cells and insulin-secreting beta cells, respectively. In both cases activated PPARδ induced adaptive responses that allowed the cells to adjust to ambient stressful metabolic conditions. This review article addresses the interactions of 4-hydroxyalkenals with PPARδ and the resulting hormetic interactions in cells exposed to nutrient overload conditions.

Topics: Aldehydes; Animals; Binding Sites; Diabetes Mellitus; Hormesis; Humans; PPAR delta

Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discussed the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective.

Topics: Aldehydes; Alzheimer Disease; Cardiovascular Diseases; Diabetes Mellitus; Disease Progression; Humans; Inflammatory Bowel Diseases; Lipid Peroxidation; Molecular Structure; Neoplasms

Elevated levels of pro-oxidants and various markers of oxidative tissue damage were found in diabetic patients, indicating involvement of oxidative stress in the pathogenesis of diabetes mellitus (DM). On one side, physiological levels of reactive oxygen species (ROS) play an important role in redox signaling of various cells, while on the other, excessive ROS production can jeopardize the integrity and physiological functions of cellular macromolecules, in particular proteins, thus contributing to the pathogenesis of DM. Reactive aldehydes, especially 4-hydroxynonenal (HNE), are considered as second messengers of free radicals that act both as signaling molecules and as cytotoxic products of lipid peroxidation causing long-lasting biological consequences, in particular by covalent modification of macromolecules. Accordingly, the HNE and related reactive aldehydes may play important roles in the pathophysiology of DM, both in the development of the disease and in its progression and complications due to the following: (i) exposure of cells to supraphysiological levels of 4-hydroxyalkenals, (ii) persistent and sustained generation of 4-hydroxyalkenals that progressively affect vulnerable cells that lack an efficient bioactive aldehyde neutralization system, (iii) altered redox signaling influenced by reactive aldehydes, in particular by HNE, and (iv) induction of extracellular generation of similar aldehydes under secondary pathological conditions, such as low-grade inflammation.

Topics: Aldehydes; Diabetes Mellitus; Free Radicals; Humans; Lipid Peroxidation; Oxidative Stress; Reactive Oxygen Species; Second Messenger Systems; Signal Transduction

Oxidative stress is implicated in the pathogenesis of numerous disease processes including diabetes mellitus, atherosclerosis, ischaemia reperfusion injury and rheumatoid arthritis. Chemical modification of amino acids in protein during lipid peroxidation results in the formation of lipoxidation products which may serve as indicators of oxidative stress in vivo. The focus of the studies described here was initially to identify chemical modifications of protein derived exclusively from lipids in order to assess the role of lipid peroxidative damage in the pathogenesis of disease. Malondialdehye (MDA) and 4-hydroxynonenal (HNE) are well characterized oxidation products of polyunsaturated fatty acids on low-density lipoprotein (LDL) and adducts of these compounds have been detected by immunological means in atherosclerotic plaque. Thus, we first developed gas chromatography-mass spectrometry assays for the Schiff base adduct of MDA to lysine, the lysine-MDA-lysine diimine cross-link and the Michael addition product of HNE to lysine. Using these assays, we showed that the concentrations of all three compounds increased significantly in LDL during metal-catalysed oxidation in vitro. The concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine (CML) also increased during LDL oxidation, while that of its putative carbohydrate precursor the Amadori compound N epsilon-(1-deoxyfructose-1-yl)lysine did not change, demonstrating that CML is a marker of both glycoxidation and lipoxidation reactions. These results suggest that MDA and HNE adducts to lysine residues should serve as biomarkers of lipid modification resulting from lipid peroxidation reactions, while CML may serve as a biomarker of general oxidative stress resulting from both carbohydrate and lipid oxidation reactions.

Topics: Aldehydes; Arteriosclerosis; Biomarkers; Diabetes Mellitus; Glycation End Products, Advanced; Humans; Lipid Peroxidation; Lipoproteins, LDL; Lysine; Maillard Reaction; Malondialdehyde; Oxidative Stress; Proteins

Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1

Topics: Aldehyde Dehydrogenase; Aldehydes; Animals; Diabetes Mellitus; Gene Knockout Techniques; Humans; Hyperglycemia; Zebrafish

We demonstrated previously that TRPV1-dependent regulation of coronary blood flow (CBF) is disrupted in diabetes. Further, we have shown that endothelial TRPV1 is differentially regulated, ultimately leading to the inactivation of TRPV1, when exposed to a prolonged pathophysiological oxidative environment. This environment has been shown to increase lipid peroxidation byproducts including 4-Hydroxynonenal (4-HNE). 4-HNE is notorious for producing protein post-translation modification (PTM) via reactions with the amino acids: cysteine, histidine and lysine. Thus, we sought to determine if 4-HNE mediated post-translational modification of TRPV1 could account for dysfunctional TRPV1-mediated signaling observed in diabetes. Our initial studies demonstrate 4-HNE infusion decreases TRPV1-dependent coronary blood flow in C57BKS/J (WT) mice. Further, we found that TRPV1-dependent vasorelaxation was suppressed after 4-HNE treatment in isolated mouse coronary arterioles. Moreover, we demonstrate 4-HNE significantly inhibited TRPV1 currents and Ca

Topics: Action Potentials; Aldehydes; Animals; Blood Flow Velocity; Calcium Signaling; Capsaicin; Cardiovascular Agents; Coronary Circulation; Coronary Vessels; Cysteine; Diabetes Mellitus; Disease Models, Animal; Femoral Artery; HEK293 Cells; Humans; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Protein Processing, Post-Translational; Signal Transduction; TRPV Cation Channels; Vasodilation

Oxidative damage is considered to play an important role in the pathogenesis of several diseases, such as diabetes mellitus (DM), atherosclerosis, cardiovascular complications and chronic renal failure. DM is associated with the oxidative stress and formation of advanced glycation end products (AGEs). Different drugs inhibit oxidative stress and formation of advanced glycation end products. Aminoguanidine (AG) has been proposed as a drug of potential benefit in prophylaxis of the complications of DM. Recent reports show a pro-oxidant activity of AG. Therefore we examined the effect of structural analogue of AG, its Schiff base with pyridoxal-pyridoxylidene aminoguanidine (PAG) on the level of selected markers of oxidative stress. We found that PAG decreased total damage to DNA in controls as well as in diabetic group of rats. However, we also found that PAG supplementation increases susceptibility of lipoproteins to oxidation and formation of conjugated dienes in both, diabetic as well as control animals. Its administration to diabetic rats decreases antioxidant capacity of plasma. Therefore, it is necessary to search for other structural modifications of AG that would combine its higher anti-diabetic activity with less toxicity.

Topics: Aldehydes; Animals; Antioxidants; Biomarkers; Diabetes Mellitus; DNA Damage; Guanidines; Lipoproteins; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Pyridoxal; Rats; Rats, Wistar; Solubility; Water

Gene class, ontology, or pathway testing analysis has become increasingly popular in microarray data analysis. Such approaches allow the integration of gene annotation databases, such as Gene Ontology and KEGG Pathway, to formally test for subtle but coordinated changes at a system level. Higher power in gene class testing is gained by combining weak signals from a number of individual genes in each pathway. We propose an alternative approach for gene-class testing based on mixed models, a class of statistical models that: a) provides the ability to model and borrow strength across genes that are both up and down in a pathway, b) operates within a well-established statistical framework amenable to direct control of false positive or false discovery rates, c) exhibits improved power over widely used methods under normal location-based alternative hypotheses, and d) handles complex experimental designs for which permutation resampling is difficult. We compare the properties of this mixed models approach with nonparametric method GSEA and parametric method PAGE using a simulation study, and illustrate its application with a diabetes data set and a dose-response data set.

Topics: Aldehydes; Area Under Curve; Cell Line, Tumor; Databases, Genetic; Diabetes Mellitus; Dose-Response Relationship, Drug; Gene Expression; Gene Expression Profiling; Humans; Linear Models; Models, Genetic; Models, Statistical; Oligonucleotide Array Sequence Analysis; Sensitivity and Specificity; Systems Biology

Diabetes mellitus evoked by streptozotocine in rats is associated with the oxidative stress. We examined the effect of Schiff's base 2,5-dihydroxybenzaldehyde with a well-known antidiabetic drug aminoguanidine, 2,5-dihydroxybenzilideneaminoguanidine (BAG) on the production of markers of oxidative stress such as 4-hydroxy-2-nonenal (4HNE) and conjugated dienes in diabetic rats. BAG administration did not affect glucose level in diabetic rats but significantly decreased the production of 4HNE and conjugated dienes. On the other hand, BAG caused the elevation of conjugated dienes and an insignificant increase of 4HNE levels in the control animals.

Topics: Aldehydes; Animals; Biomarkers; Diabetes Mellitus; Glucose; Guanidines; Lipoproteins; Male; Oxidative Stress; Rats; Rats, Wistar; Reference Values; Schiff Bases; Streptozocin

This study assesses whether the HNE accumulation we formerly observed in liver microsomes and mitochondria of BB/Wor diabetic rats depends on an increased rate of lipoperoxidation or on impairment of enzymatic removal. There are three main HNE metabolizing enzymes: glutathione-S-transferase (GST), aldehyde dehydrogenase (ALDH), and alcohol dehydrogenase (ADH). In this study we show that GST and ALDH activities are reduced in liver microsomes and mitochondria of diabetic rats; in contrast, ADH activity remains unchanged. The role of each enzyme in HNE removal was evaluated by using enzymatic inhibitors. The roles of both GST and ALDH were markedly reduced in diabetic rats, while ADH-mediated consumption was significantly increased. However, the higher level of lipohydroperoxides in diabetic liver indicated more marked lipoperoxidation. We therefore think that HNE accumulation in diabetic liver may depend on both mechanisms: increased lipoperoxidation and decreased enzymatic removal. We suggest that glycoxidation and/or hyperglycemic pseudohypoxia may be involved in the enzymatic impairment observed. Moreover, since HNE exerts toxic effects on enzymes, HNE accumulation, deficiency of HNE removal, and production of reactive oxygen species can generate vicious circles able to amplify the damage.

Topics: Aldehydes; Animals; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Glutathione Transferase; Hydrogen Peroxide; Inactivation, Metabolic; Lipid Peroxidation; Liver; Male; Microsomes, Liver; Mitochondria; Rats; Spectrophotometry