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

Department of Pediatrics , Stanford University, Palo Alto, California, United States
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 10/2003; 308(4):956-60. DOI: 10.1016/S0006-291X(03)01504-3
Source: PubMed


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.

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    • "The beneficial cardiovascular effects of aspirin are generally attributed to its immediate platelet inhibitory function. However, accumulating evidence suggest that aspirin may have additional biological properties on the vasculature that contribute to the reduction of ischemic cardiovascular events in patients with hypertension and atherosclerosis (4). "
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    ABSTRACT: Aspirin is of proven value as an antithrombotic drug. In unstable angina it reduces the risk of death and myocardial infarction by half. Most studies on the mechanism of action of aspirin have concentrated on the effect of aspirin on platelets. In the present study we have tried to prove that there is another biophysical mechanism of aspirin, and that is through the effect of aspirin on erythrocytes. In this study ten blood samples were incubated with aspirin at different concentrations. The fractal dimension of erythrocytes subjected to shear rates from 5 s(-1) to 30 s(-1), in a cone and plate device designed and constructed in our lab, was calculated by processing the images of the erythrocyte. At each shear rate, the fractal dimensions of the erythrocytes were found to be strongly correlated with aspirin concentration. It is suggested that further studies using different biophysical methods must be carried out to detect the other mechanisms underlying the effect of aspirin on different blood cells.
    09/2012; 8(3):188-193.
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    • "The present findings are consistent with those reported by Grosser et al. (2003) and Oberle et al. (2002), that HO-1 amplifies the therapeutic effects of certain stimuli in animals, such as aspirin and pentaerythrityl trinitrate (PETN), a long-acting NO donor. Subsequent experiments showed that the potent HO-1 inhibitor ZnPPIX (Supplementary Fig. S2 at JXB online) could block responses of SA and haemin in the induction of MSHO1 gene expression (Fig. 3), alleviating overproduction of TBARS (Fig. 1) and oxidative stress (Supplementary Fig. S3 at JXB online), as well as lowering the Cd toxicity (Fig. 2). "
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    ABSTRACT: This work examines the involvement of haem oxygenase-1 (HO-1) in salicylic acid (SA)-induced alleviation of oxidative stress as a result of cadmium (Cd) stress in alfalfa (Medicago sativa L.) seedling roots. CdCl(2) exposure caused severe growth inhibition and Cd accumulation, which were potentiated by pre-treatment with zinc protoporphyrin (ZnPPIX), a potent HO-1 inhibitor. Pre-treatment of plants with the HO-1 inducer haemin or SA, both of which could induce MsHO1 gene expression, significantly reduced the inhibition of growth and Cd accumulation. The alleviation effects were also evidenced by a decreased content of thiobarbituric acid-reactive substances (TBARS). The antioxidant behaviour was confirmed by histochemical staining for the detection of lipid peroxidation and the loss of plasma membrane integrity. Furthermore, haemin and SA pre-treatment modulated the activities of ascorbate peroxidase (APX), superoxide dismutase (SOD), and guaiacol peroxidase (POD), or their corresponding transcripts. Significant enhancement of the ratios of reduced/oxidized homoglutathione (hGSH), ascorbic acid (ASA)/dehydroascorbate (DHA), and NAD(P)H/NAD(P)(+), and expression of their metabolism genes was observed, consistent with a decreased reactive oxygen species (ROS) distribution in the root tips. These effects are specific for HO-1, since ZnPPIX blocked the above actions, and the aggravated effects triggered by SA plus ZnPPIX were differentially reversed when carbon monoxide (CO) or bilirubin (BR), two catalytic by-products of HO-1, was added. Together, the results suggest that HO-1 is involved in the SA-induced alleviation of Cd-triggered oxidative stress by re-establishing redox homeostasis.
    Journal of Experimental Botany 08/2012; 63(15):5521-34. DOI:10.1093/jxb/ers201 · 5.53 Impact Factor
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    • "It consists of ASA and a -ONO2 group connected through a spacer and is in preclinical development, however, there are some contrary reports to current beliefs (9). ASA is known to exert antioxidant effects by unidentified mechanisms (10). The data from recent experiments proposing that one of ASA roles in inflammation is the induction of NO, which potently inhibits leukocyte /endothelium interaction during acute inflammation. "
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    ABSTRACT: The purpose of this study was to evaluate antileishmanial effects of ASA via NO pathway in Leishmania major infected Balb/c mice. Moreover, toxicity and pathological consequences of ASA administration were investigated. Balb/c mice were infected with L. major and ASA was inoculated orally after lesion appearance for its ability to modulate NO and to modify Leishmania infection in host, in order to evaluate the effects of NO production on size and lesion macroscopy, delay of lesion formation and proliferation of amastigotes inside macrophages. Liver, spleen, and lymph nodes were also studied as target organs to detect amastigotes. In addition, plasma was investigated for NO induction using Griess microassay. ASA increased NO production in plasma of both naïve and Leishmania test groups at the ultimate of the experimental period. A decline was observed in proliferation of amastigotes inside macrophages of test group when compared with control one. ASA reduced lesion size, inhibited Leishmania visceralisation in spleen, lymph node, and decreased hepato/splenomegaly in ASA treated animals. Some antileishmanial effects of ASA by NO-modulation were indicated during systemic leishmaniasis in mice. Despite slight effects on lesion size, ASA decreased parasite visceralization in target organs and declined their proliferation inside macrophages. Therefore, ASA may be indicated to inhibit systemic leishmaniasis via NO pathway in mice model.
    02/2012; 7(2):21-8.
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