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. 2009 Nov 23;4(11):e7959.
doi: 10.1371/journal.pone.0007959.

V体育安卓版 - Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation

Jean-Marie Launay  1 , Muriel Del Pino, Gilles Chironi, Jacques Callebert, Katell Peoc'h, Jean-Louis Mégnien, Jacques Mallet, Alain Simon, Francine Rendu
Affiliations

Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation

Jean-Marie Launay et al. PLoS One. .

Abstract

Background: Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years VSports手机版. .

Methodology/principal findings: 5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)--the 5-HT/MAO catabolite--in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0. 01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0. 00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0. 001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0. 0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity V体育安卓版. .

Conclusions/significance: This is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health V体育ios版. .

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Conflict of interest statement (V体育ios版)

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Platelet 5-HT catabolism according to smoking status.
PRP 5-HT (1A) and PPP 5-HIAA (1B) were measured by HPLC in samples of 34 NS, 44 S and 37 FS. Results are means as nmoles 5-HT/109 platelets and as nM 5-HIAA. Bars represent standard deviations. Significance: *P<0.001. None of the patients studied had a storage pool disease (<0.5 nmoles/109 platelets). Platelet MAO-B activities (1C) were determined on PRP samples of 34 NS, 44 S and 37 FS by radioenzymology. Results are given as nmoles of substrate per mg protein and per hour. Platelet MAO-B protein concentrations (1D) were assessed both by Western blot and by measuring the binding of a reversible inhibitor of MAO-B to platelet membranes of 34 NS, 44 S and 37 FS and are expressed as pmoles of MAO-B per mg platelet protein. Results are mean values and bars represent standard deviations. Significance: *P<0.001; ‡P<0.00001.
Figure 2
Figure 2. Serotonin catabolism, cardiovascular risk and smoking status.
Correlations between (A) the Framingham Risk score and platelet 5-HT contents (n = 100, r = 0.27, P<0.01) or plasma 5-HIAA levels (n = 101, r = −0.25, P<0.02) and between (B) MAO-B amount and smoking duration (n = 101, r = 0.25, P<0.02).
Figure 3
Figure 3. Analysis of the MAOB gene promoter methylation status.
A Left: methylation frequencies at each CpG site within the human MAOB gene core promoter. Values (%) are means for each group (4 NS, 5 S, and 4 FS). A Right: mean methylation frequency of the 22 CpG sites of the MAOB gene promoter according to the smoking status (4 NS, 5 S, 4 FS) (*P<0.0001). B: correlation between the mean methylation frequencies of the MAOB gene promoter 22 CpG sites and the platelet MAO amounts (n = 13, r = 0.70, P<0.001). Insert: PBMC MAO-B activity (nmoles.mg protein−1.h−1) and protein concentrations (pmoles.mg protein−1) according to the smoking status of the subjects in the genetic study (4 NS, 5 S, 4 FS). Significance: *P<0.001.
Figure 4
Figure 4. Effect of cigarette smoke on DNA methyltransferase and nucleic acid demethylase activities in mice.
Mice (10 per group) were exposed (Sm) or not (NSm) to cigarette smoke and enzyme activities (A: MAO-A and MAO-B, B: DNA methyltransferase, and C: nucleic acid demethylase) determined on lung extracts as described in the methods. Results are expressed as means ± SD. Insert: platelet MAO activities (nmoles.mg protein−1.h−1) and protein concentrations (pmoles.mg protein−1) according to the smoking status of mice. Significance: *P<0.001
Figure 5
Figure 5. Effect of cigarette smoke on serotonin (5-HT) catabolism.
Cigarette smoke stimulates the nucleic acid demethylase activity (1.) which generates aldehydes (HCHO) and demethylates the MAO promoter gene (2.). The demethylated MAO promoter gene leads to increased MAO protein concentration (4). The aldehydes, by their action on methylene tetrahydrofolate reductase (3. MTHFR), lead to the formation of β-carbolines, such as harman and norharman, from 5-HT. Harman and norharman are inhibitors of MAO activity (5.) and, being present in cigarette smoke*, keep the sequence 1–5 switched on in smokers. The β-carbolines also act on GABA-A receptors, thus contributing to mood regulation. *The in vivo levels of plasma harman (6.8 nM) and norharman (20.02 nM) reported in smokers might also be high enough to stimulate nucleic acid demethylase activity, as it is the case for platelet MAO-B inhibition .
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