4-hydroxy-2-nonenal and Hyperlipidemias

Since the landmark discovery of α,β-unsaturated 4-hydroxyalkenals by Esterbauer and colleagues most studies have addressed the consequences of the tendency of these lipid peroxidation products to form covalent adducts with macromolecules and modify cellular functions. Many studies describe detrimental and cytotoxic effects of 4-hydroxy-2E-nonenal (4-HNE) in myriad tissues and organs and many pathologies. Other studies similarly assigned unfavorable effects to 4-hydroxy-2E-hexenal (4-HHE) and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE). Nutrient overload (e.g., hyperglycemia, hyperlipidemia) modifies lipid metabolism in cells and promotes lipid peroxidation and the generation of α,β-unsaturated 4-hydroxyalkenals. Advances glycation- and lipoxidation end products (AGEs and ALEs) have been associated with the development of insulin resistance and pancreatic beta cell dysfunction and the etiology of type 2 diabetes and its peripheral complications. Less acknowledged are genuine signaling properties of 4-hydroxyalkenals in hormetic processes that provide defense against the consequences of nutrient overload. This review addresses recent findings on such lipohormetic mechanisms that are associated with lipid peroxidation in pancreatic beta cells. This article is part of a Special Issue entitled SI: LIPID OXIDATION PRODUCTS, edited by Giuseppe Poli.

Topics: Aldehydes; Animals; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Glycation End Products, Advanced; Hormesis; Humans; Hyperglycemia; Hyperlipidemias; Insulin Resistance; Insulin-Secreting Cells; Lipid Peroxidation; Oxidative Stress; Phospholipases A2

Metabolic syndrome (MetS) is a predictor of cardiovascular diseases, commonly associated with oxidative stress and inflammation. However, the pathogenic mechanisms are not yet fully elucidated. The aim of the study is to evaluate the oxidative status and inflammation in the heart of obese Zucker rats (OZRs) and lean Zucker rats (LZRs) at different ages. Morphological and morphometric analyses were performed in the heart. To study the oxidative status, the malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), protein oxidation, and antioxidant enzymes were measured in plasma and heart. To elucidate the inflammatory markers involved, immunohistochemistry and Western blot were performed for cellular adhesion molecules and proinflammatory cytokines. OZRs were characterized by hypertension, hyperlipidemia, hyperglycemia, and insulin resistance. The obesity increased MDA and decreased the activities of superoxide dismutase (SOD) in plasma as well as in the heart, associated with cardiomyocytes hypertrophy. OxyBlot in plasma and in heart showed an increase of oxidativestate proteins in OZRs. Vascular cell adhesion molecule-1, interleukin-6, and tumor necrosis factor-α expressions in OZRs were higher than those of LZRs. However, these processes did not induce apoptosis or necrosis of cardiomyocytes. Thus, MetS induces the lipid peroxidation and decreased antioxidant defense that leads to heart tissue changes and coronary inflammation.

Topics: Aldehydes; Animals; Antioxidants; Cardiovascular System; Cytokines; Disease Models, Animal; Heart; Hyperglycemia; Hyperlipidemias; Hypertension; Inflammation; Insulin Resistance; Male; Malondialdehyde; Metabolic Syndrome; Obesity; Oxidative Stress; Rats; Rats, Zucker; Superoxide Dismutase

Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway. In diabetes, it is related to microvascular complications. We discovered AR expression in foam cells by gene chip screening and hypothesized that it may be relevant in atherosclerosis.. AR gene expression and activity were found to be increased in human blood monocyte-derived macrophages during foam cell formation induced by oxidized LDL (oxLDL, 100 microg/mL). AR activity as photometrically determined by NADPH consumption was effectively inhibited by the AR inhibitor epalrestat. oxLDL-dependent AR upregulation was further increased under hyperglycemic conditions (30 mmol/L D-glucose) as compared to osmotic control, suggesting a synergistic effect of hyperlipidemia and hyperglycemia. AR was also upregulated by 4-hydroxynonenal, a constituent of oxLDL. Upregulation was blocked by an antibody to CD36. AR inhibition resulted in reduction of oxLDL-induced intracellular oxidative stress as determined by 2'7'-dichlorofluoresceine diacetate (H2DCFDA) fluorescence, indicating that proinflammatory effects of oxLDL are partly mediated by AR. Immunohistochemistry showed AR expression in CD68+ human atherosclerotic plaque macrophages.. These data show that oxLDL-induced upregulation of AR in human macrophages is proinflammatory in foam cells and may represent a potential link among hyperlipidemia, atherosclerosis, and diabetes mellitus.

Topics: Adult; Aldehyde Reductase; Aldehydes; Atherosclerosis; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Foam Cells; Humans; Hyperlipidemias; Lipoproteins, LDL; Male; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Rhodanine; Risk Factors; Thiazolidines; Up-Regulation

Both plasma and whole blood concentrations of 4-hydroxy-2-nonenal (4HNE) were significantly elevated in a population (n = 6) of 2 year old Watanabe heritable hyperlipidemic rabbits relative to a population (n = 6) of New Zealand White rabbits. The plasma concentrations were 74 +/- 10 nmol/L for the Watanabe group and 47 +/- 6 nmol/L for the New Zealand White group. The whole blood concentrations were 364 +/- 55 nmol/L for the Watanabe group and 188 +/- 64 nmol/L for the New Zealand White group. These results indicate that 4HNE concentrations in blood can be elevated in individuals with atherosclerosis and demonstrate the potential link between the formation of 4HNE and the progression of atherosclerosis.

Topics: Aldehydes; Animals; Cholesterol; Hyperlipidemias; Rabbits; Reference Values; Species Specificity