Procainamide Inhibits DNA Methylation and Alleviates Multiple Organ Dysfunction in Rats with Endotoxic Shock.
Excessive inflammatory and oxidative stress lead to circulatory failure, multiple organ dysfunction, and high mortality in patients with sepsis. Microbial infection-induced DNA hypermethylation is associated with the augmentation of inflammation and oxidative stress. In our previous study, the antiarrhythmic drug procainamide inhibits the expression of DNA methyltransferase 1 (DNMT1) and diminishes IL-6 levels in rats with rhabdomyolysis. Thus, we further evaluated the effects of procainamide on the development of circulatory failure and multiple organ dysfunction in rats with endotoxic shock. Male Wistar rats were intravenously infused with saline or lipopolysaccharide (LPS) followed by procainamide administration. The changes of hemodynamics, blood glucose, biochemical variables, and plasma nitric oxide (NO) levels were analyzed during the experimental period. At the end of experiments, animal organs were also obtained for examining superoxide production, neutrophil infiltration, and DNA methylation status. Our results showed that LPS induced circulatory failure, multiple organ dysfunction, and high mortality rate in endotoxemic rats. Overt neutrophil infiltration and superoxide production, accompanied by the elevations of DNMT1 and 5-methylcytosine levels in the lung of endotoxemic rats were also observed. Treatment of endotoxemic animals with procainamide not only inhibited the increased levels of DNMT1 and 5-methylcytosine but also ameliorated neutrophil infiltration and superoxide production in the lung. In addition, the anti-inflammatory gene, IL27RA, was down-regulated in the LPS group and up-regulated in the LPS + Procainamide group. Procainamide also diminished IL27RA methylation in the lung of endotoxemic rat. Moreover, both DNMT inhibitors procainamide and hydralazine improved hypotension, hypoglycemia, and multiple organ dysfunction of LPS-treated rats. Thus, we suggest that the beneficial effects of procainamide could be attributed to the suppression of DNA methylation, neutrophil infiltration, superoxide production, and NO formation. It seems that this old drug may have new potential uses in infectious diseases, in particular, associated with endotoxemia.
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, R.O.C., Taiwan.|Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Chih-Chin
CC
Shih
Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Mei-Hui
MH
Liao
Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Tsan-Seng
TS
Hsiao
Department of Surgery, Chi Mei Medical Center, Tainan, R.O.C., Taiwan.
Hiong-Ping
HP
Hii
Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, R.O.C., Taiwan.|School of Medicine, National Yang-Ming University, Taipei, R.O.C., Taiwan.
Ching-Hui
CH
Shen
Department of Physiology, National Defense Medical Center, Taipei, R.O.C., Taiwan.|Department of Nursing, University of Kang-Ning, Taipei, R.O.C., Taiwan.|Department of Health Management for Elderly Society, University of Kang-Ning, Taipei, R.O.C., Taiwan.
Shiu-Jen
SJ
Chen
Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Shuk-Man
SM
Ka
Department of Biochemistry, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Yung-Lung
YL
Chang
Department of Pharmacology, National Defense Medical Center, Taipei, R.O.C., Taiwan.
Chin-Chen
CC
Wu
J Immunol. 1988 Apr 1;140(7):2197-200
3258330
J Clin Invest. 2014 Jul;124(7):3187-99
24865430
Int J Mol Sci. 2015 Jun 03;16(6):12560-77
26047341
Mol Med Rep. 2013 May;7(5):1417-24
23546543
Carcinogenesis. 2012 Jul;33(7):1286-93
22552403
Am J Pathol. 2014 Jun;184(6):1807-18
24726498
J Pharmacol Exp Ther. 2000 Jun;293(3):829-36
10869382
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4681-5
9114051
Lab Invest. 2011 Jun;91(6):825-36
21242958
Eur J Pharmacol. 2002 May 10;442(3):265-72
12065080
Mol Cell Biochem. 2013 Feb;374(1-2):203-11
23160801
Nat Genet. 2003 Jun;34(2):187-92
12740577
Mol Cancer Res. 2012 Jan;10(1):40-51
22064654
Environ Mol Mutagen. 2013 Jul;54(6):421-8
23813549
Biochim Biophys Acta. 1999 May 5;1411(2-3):437-55
10320674
Diabetologia. 2012 Feb;55(2):509-19
22086159
Crit Care Med. 2008 Jun;36(6):1864-72
18496380
Circulation. 2010 Jun 22;121(24):2661-71
20529999
J Cell Physiol. 2008 Oct;217(1):207-14
18481258
Epigenetics. 2014 Sep;9(9):1302-16
25147914
PLoS One. 2013 Jul 09;8(7):e67342
23874414
Ann Intern Med. 2001 Apr 3;134(7):573-86
11281740
Nat Immunol. 2006 Sep;7(9):929-36
16906167
Clin Cancer Res. 2003 May;9(5):1596-603
12738711
Mitochondrion. 2004 Sep;4(5-6):729-41
16120428
J Clin Pathol. 2011 Aug;64(8):677-82
21617174
Cancer Res. 2001 Dec 15;61(24):8611-6
11751372
PLoS Pathog. 2014 May 08;10(5):e1004110
24809349
Nat Rev Genet. 2012 May 29;13(7):484-92
22641018
DNA Repair (Amst). 2004 Feb 3;3(2):155-61
14706349
Nat Rev Immunol. 2008 Oct;8(10):776-87
18802444
Br J Anaesth. 2011 Jul;107(1):57-64
21596843
J Biol Chem. 2005 Dec 9;280(49):40749-56
16230360
PLoS One. 2016 Feb 26;11(2):e0150319
26918767
Virulence. 2014 Jan 1;5(1):36-44
23774844
Ann Rheum Dis. 2010 Aug;69(8):1502-10
20511611
Immunity. 2003 Nov;19(5):645-55
14614852
J Pharmacol Exp Ther. 2006 Oct;319(1):73-81
16815867
Cell Mol Life Sci. 2014 Mar;71(6):1045-54
24132510
Endocrinology. 2014 Dec;155(12 ):4925-38
25251587
EMBO Rep. 2011 Jul 01;12(7):647-56
21660058
Hum Mol Genet. 2000 Oct;9(16):2395-402
11005794
J Gastroenterol. 2010;45(1):37-44
19821005
J Cell Sci. 2004 Jun 15;117(Pt 14):2865-7
15197240
Epigenetics. 2013 Dec;8(12 ):1261-7
24135723
N Engl J Med. 2013 Aug 29;369(9):840-51
23984731
Epigenomics. 2012 Apr;4(2):229-35
22449193
Toxicol Lett. 2014 Mar 21;225(3):488-97
24440346