18203850

pubmed:Citation

3

Our group (Patschan S, Chen J, Gealekman O, Krupincza K, Wang M, Shu L, Shayman JA, Goligorsky MS; Am J Physiol Renal Physiol 294: F100-F109, 2008) previously observed an accumulation of gangliosides coincident with development of cell senescence and demonstrated lysosomal permeabilization in human umbilical vein endothelial cells exposed to glycated collagen I (GC). Therefore, we investigated whether the lysosome-dependent, caspase-independent or type 2-programmed cell death (autophagy) is involved in development of premature senescence of endothelial cells. The cleaved microtubule-associated protein 1 light-chain 3 (LC3), a marker of autophagosome formation, was overexpressed within 24 h of GC treatment; however, by 4-5 days, it was nearly undetectable. Early induction of autophagosomes was associated with their fusion with lysosomes, a phenomenon that later became subverted. Autophagic cell death can be triggered by the products of damaged plasma membrane, sphingolipids, and ceramide. We observed a clustering of membrane rafts shortly after exposure to GC; later, after 24 h, we observed an internalization, accompanied by an increased acid sphingomyelinase activity and accumulation of ceramide. Pharmacological inhibition of autophagy prevented development of premature senescence but did lead to the enhanced rate of apoptosis in human umbilical vein endothelial cells exposed to GC. Pharmacological induction of autophagy resulted in reciprocal changes. These observations appear to represent a mechanistic molecular cascade whereby advanced glycation end products like GC induce sphingomyelinase activity, accumulation of ceramide, clustering, and later internalization of lipid rafts.

eng

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MEDLINE

0363-6135

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H1119-29

pubmed-meshheading:18203850-Aging, pubmed-meshheading:18203850-Apoptosis, pubmed-meshheading:18203850-Autophagy, pubmed-meshheading:18203850-Cells, Cultured, pubmed-meshheading:18203850-Ceramides, pubmed-meshheading:18203850-Chromatography, High Pressure Liquid, pubmed-meshheading:18203850-Endothelial Cells, pubmed-meshheading:18203850-Fluorescent Antibody Technique, pubmed-meshheading:18203850-Humans, pubmed-meshheading:18203850-Immunohistochemistry, pubmed-meshheading:18203850-Indicators and Reagents, pubmed-meshheading:18203850-Lipids, pubmed-meshheading:18203850-Lysophospholipids, pubmed-meshheading:18203850-Lysosomes, pubmed-meshheading:18203850-Membrane Microdomains, pubmed-meshheading:18203850-Microtubule-Associated Proteins, pubmed-meshheading:18203850-Phenotype, pubmed-meshheading:18203850-Sphingomyelin Phosphodiesterase, pubmed-meshheading:18203850-Sphingosine, pubmed-meshheading:18203850-Stress, Physiological

Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural