The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No. 3 • June 2010


Chronic Obstructive Pulmonary Disease
Decreased Histone Deacetylase Activity Results in
Resistance to Antiinflammatory Effect of
Corticosteroids in COPD

COPD (which is usually but not always caused by cigarette smoking) is associated with chronic severe airway inflammation (greater in patients with advanced disease) that is resistant to the antiinflammatory effects of corticosteroids. It has been recently discovered that histone deacetylase 2 (HDAC2) activity is reduced in the lungs of COPD patients1-3 and this is thought to possibly play a key role in the severe inflammation in COPD that is difficult to control. Normally, corticosteroids recruit HDAC2 to an activated coactivator complex, which then switches off the process that allows gene transcription and synthesis of inflammatory proteins.1 However, in those with impaired HDAC2 activity, corticosteroids may not be effective in reducing inflammatory protein synthesis. So whereas treatment with corticosteroids can reduce inflammation in asthma, in COPD they usually provide much less benefit.1

“Gene expression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT [histone acetyltransferase] activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. ... In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrosative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients, and cystic fibrosis.”2 Histones are proteins that surround DNA, regulating access to genes to either allow or prevent transcription. Histone deacetylases, by removing acetyl groups from hyperacetylated histones, suppress gene transcription.2

Carbonyl Compounds Antagonize HDAC1, HDAC2, and HDAC3

A 2010 paper4 has now reported that alkylation (carbonylation) of conserved cysteines in the protein structure of certain HDACs (HDAC1, HDAC2, and HDAC3) antagonizes their transcriptional repressor function. Carbonyl compounds that result from protein and lipid oxidation processes can act as powerful inducers of the formation of AGEs (advanced glycation endproducts, markers of carbonyl stress), implicated as causative factors in cardiovascular disease, cancer, complications of diabetes, and aging (AGEs increase with age). Hence, one potential way to help prevent the decrease in HDAC2 in COPD is to take supplements that scavenge carbonyls involved in the formation of AGEs. Our AGEless™ formulation contains several natural products that potently scavenge carbonyl compounds and/or inhibit the formation of and/or damage caused by AGEs including thiamine,11 pyridoxine hydrochloride, bentofiamine (lipid soluble thiamine),12 carnosine,4a histidine,4b alpha-lipoic acid,4c and rutin. L-arginine (which we take as part of our InnerPower Plus™ formulation) has also been shown to attenuate the accelerated age-dependent accumulation of AGEs in hamsters with hyperglycemia and hyperlipidemia.4d [See “Reducing Glycation Reactions for Better Health and Longer Life” in the February, 2008 issue of Life Enhancement.]

Curcumin has also been found to restore corticosteroid function in human monocytes exposed to oxidants in vitro by maintaining HDAC2.5 The authors of this paper propose that “[c]urcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.”

The methylxanthine theophylline (with a related chemical structure to caffeine) has also been reported to induce histone deacetylase (HDAC) activity at low doses in human studies6,7 to decrease inflammatory gene expression.

Green and black tea extracts have been reported to have trapping effects on peroxidation-derived carbonyl substances in seal blubber oil.9 (Just in case you are enjoying a meal of seal blubber any time soon.) The researchers were studying whether green and black tea extracts could stabilize marine oils from lipid peroxidation that created carbonyls. The extracts did in fact reduce significantly the production of acrolein and malondialdehyde, two reactive carbonyl species, resulting from lipid peroxidation in the seal blubber oil.

Cruciferous vegetables (such as broccoli and cauliflower) induce elevated levels of carbonyl-metabolizing enzymes, thus providing protection against carbonyl stress.10

Cinnamon proanthocyanidins have been found to be potent scavengers of dicarbonyls and to inhibit the formation of three typical AGEs (pentosidine, methylglyoxal, and N-(carboxymethyl)lysine.13

Finally, it is interesting to note that histone deacetylase,3 which is one of the HDACs with reduced activity as a result of carbonylation,4 has been reported to have a “unique role” in maintaining cardiac energy metabolism in mice.8 COPD patients are at increased risk of cardiovascular disease; it would be interesting to know whether HDAC3 activity is also reduced in COPD.

References

1. Barnes et al. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J 25(3):552-63 (2005).
2. Ito et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 352(19):1967-76 (2005).
3. Barnes et al, Hypothesis: Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet 363(9410):731-3 (2004).
4. Doyle and Fitzpatrick. Redox signaling, alkylation (carbonylation) of conserved cysteines inactivates Class I histone deacetylases 1, 2, and 3 and antagonizes their transcriptional repressor function. J Biol Chem 285(23):17417-24 (2010).
4a. Hipkiss. On the enigma of carnosine’s anti-ageing actions. Exp Gerontol 44(4):237-42 (2009).
4b. Lee et al. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol 513(1-2):145-50 (2005).
4c. Bierhaus et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46(9):1481-90 (1997).
4d. Georgescu and Popov. Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipidemia and hyperglycemia, a process attenuated by L-arginine. J Amer Aging Assoc 23(1):33-40 (2000).
5. Meja et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol 39(3):312-23 (2008).
6. Ito et al. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 99(13):8921-6 (2002).
7. Cosio et al. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200(5):689-95 (2004).
8. Montgomery et al. Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice. J Clin Invest 118(11):3588-97 (2008) doi:10.1172/JCI35847.
9. Zhu et al. Trapping effects of green and black tea extracts on peroxidation-derived carbonyl substances of seal blubber oil. J Agric Food Chem 57(3):1065-9 (2009).
10. Ellis. Reactive carbonyls and oxidative stress: potential for therapeutic intervention. Pharmacol Ther 115(1):13-24 (2007).
11. Shangari et al. Hepatocyte susceptibility to glyoxal [a reactive dicarbonyl] is dependent on cell thiamin content. Chem Biol Interact 165(2):146-154 (2007). “Under thiamin deficient conditions a non-toxic dose of glyoxal (2mM) became cytotoxic ...”
12. Stirban et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 29(9):2064-71 (2006).
13. Peng et al. Beneficial effects of cinnamon proanthocyanidins on the formation of specific advanced glycation endproducts and methylglyoxal-induced impairment on glucose consumption. J Agric Food Chem 58(11):6692-6 (2010).

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