3.3 Protein Methylation in Asthma and COPD
There is limited data on the role of arginine and lysine methylation in asthma and
COPD. With respect to arginine methylation, one study reports the expression levels
of protein arginine methyltransferase (PRMT) isoforms 1–6 in an animal model of
asthma [106]. Except for PRMT4, the expression of all other PRMTs was found to
be increased. In asthmatic rats, PRMT1 expression was especially high in epithelial
cells [107]. The epithelial cells also expressed and secreted more eosinophilattracting chemokines and fibroblast-activating cytokines. Consequently, the fibroblast proliferated more and expressed more growth factors, most likely through
IL-1β-induced NF-κB activation [108, 109]. Interestingly, PRMT1 expression was
also increased in the fibroblasts. Furthermore, treatment of the asthmatic rats with
AMI-1 (Fig. 3), a nonselective inhibitor of PRMTs, ameliorated the observed
pulmonary inflammation, mucus secretion, and collagen generation. This indicates
that inhibition of PRMTs might be a valuable therapeutic strategy in asthma.
Another reason for PRMT inhibition in asthma is that methylated arginine in itself,
resulting from metabolic turnover of methylated proteins, is known to inhibit nitric
oxide synthase [110, 111]. This results in a decrease in nitric oxide and an increase in
reactive oxygen species, through which methylated arginine potentiates lung inflammation and airway hyperresponsiveness.
In contrast to asthma, the expression of PRMT6 is downregulated in lung tissue of
COPD patients, as well as in mice with emphysema [112]. Furthermore, restoration
of PRMT6 expression in mice exposed to cigarette smoke extract resulted in a
decrease in inflammation, apoptosis, and oxidative stress. PRMT6 expression was
restored by treatment with a lentivirus that was encoded with the PMRT6 gene. The
protective effect of PRMT6 expression indicates that COPD treatment should focus
on increasing protein methylation. However, the role of the other PRMT isoforms
and protein demethylases in COPD is as of yet unknown. Consequently, the outcome
of treatment of COPD with either PRMT or demethylase inhibitors is unpredictable.
As with HDAC inhibition, the extent of inhibition of specific isoforms of PRMTs or
demethylases will dictate the outcome. The field is thereby in need of the discovery
and testing of isoform-selective inhibitors of PRMTs and demethylases in models
of COPD.
In comparison to arginine methylation, less is known about the functional role of
lysine methylation in asthma and COPD. This is in spite of the fact that potent and
selective lysine demethylase inhibitors have been developed [113, 114]. One in vitro
study found that reduced lysine histone methylation enhances the expression of
vascular endothelial growth factor in airway smooth muscle cells from patients with
asthma, thereby playing a role in airway remodeling [115]. An in vivo study found
that restoration of lysine methylation by treatment with the potent KDM6 inhibitor
GSK-J4 (Fig. 3) ameliorated the classical hallmarks of asthma, such as airway
hyperresponsiveness, airway inflammation, and remodeling [116]. Treatment with
GSK-J4 did however not decrease the expression of the vascular endothelial growth
factor. The main explanation for the observed positive effects of GSK-J4 is that the
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
443
There is limited data on the role of arginine and lysine methylation in asthma and
COPD. With respect to arginine methylation, one study reports the expression levels
of protein arginine methyltransferase (PRMT) isoforms 1–6 in an animal model of
asthma [106]. Except for PRMT4, the expression of all other PRMTs was found to
be increased. In asthmatic rats, PRMT1 expression was especially high in epithelial
cells [107]. The epithelial cells also expressed and secreted more eosinophilattracting chemokines and fibroblast-activating cytokines. Consequently, the fibroblast proliferated more and expressed more growth factors, most likely through
IL-1β-induced NF-κB activation [108, 109]. Interestingly, PRMT1 expression was
also increased in the fibroblasts. Furthermore, treatment of the asthmatic rats with
AMI-1 (Fig. 3), a nonselective inhibitor of PRMTs, ameliorated the observed
pulmonary inflammation, mucus secretion, and collagen generation. This indicates
that inhibition of PRMTs might be a valuable therapeutic strategy in asthma.
Another reason for PRMT inhibition in asthma is that methylated arginine in itself,
resulting from metabolic turnover of methylated proteins, is known to inhibit nitric
oxide synthase [110, 111]. This results in a decrease in nitric oxide and an increase in
reactive oxygen species, through which methylated arginine potentiates lung inflammation and airway hyperresponsiveness.
In contrast to asthma, the expression of PRMT6 is downregulated in lung tissue of
COPD patients, as well as in mice with emphysema [112]. Furthermore, restoration
of PRMT6 expression in mice exposed to cigarette smoke extract resulted in a
decrease in inflammation, apoptosis, and oxidative stress. PRMT6 expression was
restored by treatment with a lentivirus that was encoded with the PMRT6 gene. The
protective effect of PRMT6 expression indicates that COPD treatment should focus
on increasing protein methylation. However, the role of the other PRMT isoforms
and protein demethylases in COPD is as of yet unknown. Consequently, the outcome
of treatment of COPD with either PRMT or demethylase inhibitors is unpredictable.
As with HDAC inhibition, the extent of inhibition of specific isoforms of PRMTs or
demethylases will dictate the outcome. The field is thereby in need of the discovery
and testing of isoform-selective inhibitors of PRMTs and demethylases in models
of COPD.
In comparison to arginine methylation, less is known about the functional role of
lysine methylation in asthma and COPD. This is in spite of the fact that potent and
selective lysine demethylase inhibitors have been developed [113, 114]. One in vitro
study found that reduced lysine histone methylation enhances the expression of
vascular endothelial growth factor in airway smooth muscle cells from patients with
asthma, thereby playing a role in airway remodeling [115]. An in vivo study found
that restoration of lysine methylation by treatment with the potent KDM6 inhibitor
GSK-J4 (Fig. 3) ameliorated the classical hallmarks of asthma, such as airway
hyperresponsiveness, airway inflammation, and remodeling [116]. Treatment with
GSK-J4 did however not decrease the expression of the vascular endothelial growth
factor. The main explanation for the observed positive effects of GSK-J4 is that the
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
443