Article

Heme oxygenase-1 induction may explain the antioxidant profile of aspirin.

Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Str. 4, Halle (Saale) 06099, Germany.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 10/2003; 308(4):956-60. DOI: 10.1016/S0006-291X(03)01504-3
Source: PubMed

ABSTRACT Aspirin is known to exert antioxidant effects by as yet unidentified mechanisms. In cultured endothelial cells derived from human umbilical vein, aspirin (30-300 microM) increased heme oxygenase-1 (HO-1) protein levels in a concentration-dependent fashion up to fivefold over basal levels. HO-1 induction was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of both carbon monoxide and bilirubin. Pretreatment with aspirin or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by aspirin were not mimicked by indomethacin, another inhibitor of cyclooxygenase. The nitric oxide (NO) synthase blocker L-NAME prevented aspirin-dependent HO-1 induction. These findings demonstrate that aspirin targets HO-1, presumably via NO-dependent pathways. Induction of HO-1 expression and activity may be a novel mechanism by which aspirin prevents cellular injury under inflammatory conditions and in cardiovascular disease.

0 Bookmarks
 · 
112 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Heme oxygenase 1 (HO-1) degrades heme and protects against oxidative stress. In vitro and animal models suggest that HO-1 is beneficial in several diseases (e.g., postoperative ileus, gastroparesis, acute pancreatitis, and colitis). However, the only drugs (i.e., hemin and heme arginate) which pharmacologically upregulate HO-1 in humans are expensive and can only be administered intravenously. Our aims were to compare the effects of placebo, aspirin, and simvastatin alone, and with α-lipoic acid, on HO-1 protein concentration and activity in humans.Methods This randomized, double-blind, placebo-controlled study compared the effects of three oral regimens administered for 7 days, i.e., placebo; aspirin (325 mg twice daily) and simvastatin (40 mg twice daily); aspirin, simvastatin, and the sodium salt of R- α-lipoic acid (NaRLA, 600 mg three times daily) on markers of HO-1 activation (i.e., plasma HO-1 protein concentration and venous monocyte HO-1 protein activity) in 18 healthy subjects (14 females). Markers of HO-1 activation were evaluated at baseline, days 2, and 7.Key ResultsBaseline HO-1 protein concentrations and activity were similar among the three groups. Compared to placebo, aspirin and simvastatin combined, or together with NaRLA did not affect HO-1 protein concentration or activity at 2 or 7 days. HO-1 protein concentrations and activity were correlated on day 7 (r = 0.75, p = 0.0004) but not at baseline and on day 2.Conclusions & InferencesAt therapeutic doses, aspirin, simvastatin, and α-lipoic acid do not increase plasma HO-1 protein concentration or venous monocyte HO-1 activity in healthy humans.
    Neurogastroenterology and Motility 07/2014; · 2.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our previous studies have described the purification and characterization of a novel plant NAD(P)-reductase like protein (RL) from the thermogenic appendix of the Sauromatum guttatum inflorescence. RL is mainly located in cytoplasm of thermogenic plants and it can act like a bistable switch. It adopts a compact conformation during heat-production and a more expanded conformation when heat is not generated. Addition of salicylic acid, a natural thermogenic inducer, at picomolar concentration to a solution of purified RL induced a discontinuous volume phase transition in which the volume of RL in the oligomeric form expanded and shrunk repeatedly every 4-5 min. In the present study using ESI-MS analysis we have demonstrated the existence of RL in the human SK-N-SH cell line and in mouse brain tissue. The molecular mass of human RL is in the same range as of its plant counterpart, 34,140 ± 34 Da. The charge state distribution of the human RL is identical to its plant counterpart from the Sauromatum appendix during heat-production. Human RL was present in the compact state when it was purified from the SK-N-SH cell line When these cells were treated with salicylic acid (10 μM) a shift to a much more compact conformation was observed. It seems that the potential of RL to respond to salicylic acid was conserved. These results may reveal the existence of a thermoregulation system that is evolutionarily conserved and is operating by conformational changes. This discovery may also represent an opportunity for a better understanding of some of the diverse functions of salicylic acid and aspirin in plants and humans.
    The Protein Journal 11/2013; 32(8). · 1.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity has become a major public health problem of global significance. Today, aspirin remains the most commonly used medication for the treatment of pyrexia, pain, inflammation and antiplatelet. The present study aims at evaluating the possible existence of a putative p53-dependent pathway underlying the aspirin-induced inhibition of adipogenesis. Cell migration assay was identified by the ability to migrate through Transwell insert. Oil Red O staining was employed to quantify adipose accumulation. The concentration of glucose and triglyceride were measured by using assay kits. The expression levels of several master regulatory molecules controlling various signal pathways were monitored using the immunoblotting techniques. Aspirin significantly inhibited preadipocyte migration and adipose accumulation. The p53-p21 signaling and the expression of differentiation marker glycerol-3-phosphate dehydrogenase were increased in a dose-dependent manner. It indicated that aspirin induced adipocyte differentiation through p53-p21 pathway. The oncogenic ERK 1/2 MAPK signaling was induced, whereas, the expression of adipogenic markers peroxisome proliferator-activated receptor γ (PPARγ), adipocyte fatty acid-binding protein (A-FABP) and inflammatory factors cyclooxygenase-2 (Cox-2), tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) were inhibited. Aspirin negatively regulated the pentose phosphate pathway (PPP) by inhibiting the expression of rate-limiting enzyme glucose-6-phosphate dehydrogenase. Knockdown the expression of oncogenic ERK 1/2 MAPK by using 10μM PD98059 significantly increased triglyceride synthesis, adipose accumulation and activated PPP, however, decreased glucose uptake. Diverted the glucose flux to PPP, rather than increased glucose uptake, was associated with adipogenesis. Down-regulated the expression of tumor suppressor p53 by 10μM pifithrin-α (PFTα) alone had no effect on adipose accumulation. However, administration of aspirin accompanied with PFTα abolished aspirin-induced inhibition of adipogenesis. We demonstrated that aspirin-induced inhibition of adipogenesis was p53-dependent and associated with inactivation of PPP. Blockade PPP may be a novel strategy for obesity prevention and therapy. Moreover, when use aspirin in therapeutic strategy, the p53 status should be considered.
    European journal of pharmacology 04/2014; · 2.59 Impact Factor