Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2.
Efficient functioning of maintenance and repair processes seem to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, under control of several genes termed vitagenes. These include members of the heat shock protein system, and there is now evidence that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human conditions, including inflammation, neurodegenerative disorders, and aging. Among the various heat shock proteins, heme oxygenase-1 has received considerable attention; it has been recently demonstrated that heme oxygenase-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, we report here that treatment of astrocytes with acetyl-L-carnitine induces heme oxygenase-1 in a dose- and time-dependent manner and that this effect was associated with up-regulation of heat shock protein 60 as well as high expression of the redox-sensitive transcription factor Nrf2 in the nuclear fraction of treated cells. In addition, we show that addition of acetyl-L-carnitine to astrocytes, prior to proinflammatory lipopolysaccharide- and interferon-gamma-induced nitrosative stress, prevents changes in mitochondrial respiratory chain complex activity, protein nitrosation and antioxidant status induced by inflammatory cytokine insult. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases.
Calabrese
Vittorio
V
Department of Chemistry, Biochemistry and Molecular Biology Section, Faculty of Medicine, University of Catania, Catania, Italy. calabres@mbox.unict.it
Ravagna
Agrippino
A
Colombrita
Claudia
C
Scapagnini
Giovanni
G
Guagliano
Eleonora
E
Calvani
Menotti
M
Butterfield
D Allan
DA
Giuffrida Stella
Anna Maria
AM
D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018834:Chaperonin 60 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004843:Epistasis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D005949:Glucose Oxidase / Q000633:toxicity; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051267:NF-E2-Related Factor 2; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018834:Chaperonin 60; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D018697:Nootropic Agents; D011524:Protoporphyrins; D012333:RNA, Messenger; D015534:Trans-Activators; C017803:zinc protoporphyrin; C002744:3-nitrotyrosine; D014443:Tyrosine; D000108:Acetylcarnitine; D007371:Interferon-gamma; D005949:Glucose Oxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1