elastin and 4-hydroxy-2-nonenal

Vascular aging is associated with structural and functional modifications of the arteries, and by an increase in arterial wall thickening in the intima and the media, mainly resulting from structural modifications of the extracellular matrix (ECM) components. Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA), (4-hydroxynonenal, malondialdehyde, acrolein), form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging. The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that 4-HNE-histidine-adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by 4-HNE. These data indicate a complex role for lipid peroxidation and in particular for 4-HNE in elastin homeostasis, in the vascular wall remodeling during aging and atherosclerosis development.

Topics: Adult; Aged; Aged, 80 and over; Aging; Aldehydes; Aorta; Atherosclerosis; Autopsy; Elastin; Extracellular Matrix; Fatty Acids, Unsaturated; Female; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress

Chronic exposure to ultraviolet (UV) radiation causes oxidative stress, which is involved in photoaging and actinic elastosis. UV and reactive oxygen species generate lipid peroxidation products, including the α, β-unsaturated carbonyl compounds such as acrolein or 4-hydroxynonenal (4-HNE). These aldehydes can modify proteins of the extracellular matrix, but their role in the pathogenesis of photoaging is not clarified. The aim of this study was to investigate whether these aldehydes contribute to alter elastin metabolism and whether topical carbonyl scavengers delay UV-induced skin photoaging. Hairless mice (4-6-week old) daily exposed to UV-A (20 J cm(-2) per day, up to 600 J cm(-2)) exhibited the typical features of photoaging, associated with a significant increase in 4-HNE- and acrolein-adduct content, and elastotic material deposition. Immunofluorescence studies showed the accumulation of 4-HNE adducts on elastin in the dermis of UV-A-exposed mice. This was mimicked in vitro by incubating orcein-elastin with 4-HNE or acrolein, which altered its digestion by leukocyte-elastase, a feature possibly involved in the accumulation of elastotic material. A daily topical application of carnosine completely reversed the development of photoaging alterations and 4-HNE-adduct formation on elastin. These data emphasize the role of 4-HNE and acrolein in the mechanism of photoaging, and the preventive effect of carbonyl scavengers.

Topics: Aldehydes; Animals; Carnosine; Disease Models, Animal; Elasticity; Elastin; Lipid Peroxidation; Mice; Mice, Hairless; Oxidative Stress; Photosensitivity Disorders; Random Allocation; Sensitivity and Specificity; Skin Aging; Ultraviolet Rays

Elastin is a long-lived protein and a key component of connective tissues. The tissular elastin content decreases during chronological aging, and the mechanisms underlying its slow repair are not known. Lipid oxidation products that accumulate in aged tissues may generate protein dysfunction. We hypothesized that 4-hydroxynonenal (4-HNE), a highly reactive α,β-aldehydic product generated from polyunsaturated fatty acid peroxidation, could contribute to inhibiting elastin repair by antagonizing the elastogenic signaling of transforming growth factor-β1 (TGF-β1) in skin fibroblasts. We report that a low 4-HNE concentration (2µmol/L) inhibits the upregulation of tropoelastin expression stimulated by TGF-β1 in human and murine fibroblasts. The study of signaling pathways potentially involved in the regulation of elastin expression showed that 4-HNE did not block the phosphorylation of Smad3, an early step of TGF-β1 signaling, but inhibited the nuclear translocation of Smad2. Concomitantly, 4-HNE modified and stimulated the phosphorylation of the epidermal growth factor receptor (EGFR) and subsequently ERK1/2 activation, leading to the phosphorylation/stabilization of the Smad transcriptional corepressor TGIF, which antagonizes TGF-β1 signaling. Inhibitors of EGFR (AG1478) and MEK/ERK (PD98059), and EGFR-specific siRNAs, reversed the inhibitory effect of 4-HNE on TGF-β1-induced nuclear translocation of Smad2 and tropoelastin synthesis. In vivo studies on aortas from aged C57BL/6 mice showed that EGFR is modified by 4-HNE, in correlation with an increased 4-HNE-adduct accumulation and decreased elastin content. Altogether, these data suggest that 4-HNE inhibits the elastogenic activity of TGF-β1, by modifying and activating the EGFR/ERK/TGIF pathway, which may contribute to altering elastin repair in chronological aging and oxidative stress-associated aging processes.

Topics: Adult; Aging; Aldehydes; Animals; Aorta; Cell Line, Transformed; Elastin; ErbB Receptors; Fibroblasts; Flavonoids; Gene Expression Regulation; Homeodomain Proteins; Humans; Lipid Peroxidation; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Primary Cell Culture; Protein Transport; Quinazolines; Repressor Proteins; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta1; Tyrphostins

Topics: Aging; Aldehydes; Animals; Elastin; ErbB Receptors; Fibroblasts; Humans; Transforming Growth Factor beta1