Cardiac-specific overexpression of metallothionein rescues nicotine-induced cardiac contractile dysfunction and interstitial fibrosis.
Cigarette smoking is a devastating risk factor for cardiovascular diseases and nicotine is believed the main toxin component responsible for the toxic myocardial effects of smoking. Nonetheless, neither the precise mechanism of nicotine-induced cardiac dysfunction nor effective treatment is elucidated. The aim of this study was to evaluate the impact of cardiac-specific overexpression of heavy metal scavenger metallothionein on myocardial geometry and mechanical function following nicotine exposure. Adult male friend virus B (FVB) wild-type and metallothionein mice were injected with nicotine (2 mg/kg/d) intraperitoneally for 10 days. Mechanical and intracellular Ca²+ properties were examined. Myocardial histology (cross-sectional area and fibrosis) was evaluated by hematoxylin and eosin (H&E) and Masson trichrome staining, respectively. Oxidative stress and apoptosis were measured by fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H₂DCFDA) fluorescence and caspase-3 activity, respectively. Nicotine exposure failed to affect the protein abundance of metallothionein. Our data revealed reduced echocardiographic contractile capacity (fractional shortening), altered cardiomyocyte contractile and intracellular Ca²+ properties including depressed peak shortening amplitude, maximal velocity of shortening/relengthening, resting and electrically-stimulated rise in intracellular Ca²+, as well as prolonged duration of relengthening and intracellular Ca²+ clearance in hearts from nicotine-treated FVB mice, the effect of which was ameliorated by metallothionein. Biochemical and histological findings depicted overt accumulation of reactive oxygen species (ROS), apoptosis and myocardial fibrosis without any change in myocardial cross-sectional area following nicotine treatment, which was mitigated by metallothionein. Taken together, our findings suggest the antioxidant metallothionein may reconcile short-term nicotine exposure-induced myocardial contractile dysfunction and fibrosis possibly through inhibition of ROS accumulation and apoptosis.
Department of Biological Pharmacy, Agricultural University of Hebei College of Life Sciences, Baoding 071001, PR China.
Nan
N
Hu
Rui
R
Guo
Xuefeng
X
Han
Baocheng
B
Zhu
Jun
J
Ren
D000818:Animals; D002118:Calcium / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects
D018722:Nicotinic Agonists; D017382:Reactive Oxygen Species; D009538:Nicotine; D008668:Metallothionein; D002118:Calcium
J Mol Cell Cardiol. 2010 Feb;48(2):367-78
19914257
Neurotoxicol Teratol. 2003 Nov-Dec;25(6):731-6
14624973
Toxicol Appl Pharmacol. 2009 Aug 1;238(3):209-14
19236887
Diabetes. 2007 Sep;56(9):2201-12
17575086
J Clin Invest. 1997 Sep 15;100(6):1501-6
9294117
Am J Physiol Heart Circ Physiol. 2005 Jun;288(6):H2878-86
15665050
Congest Heart Fail. 2002 May-Jun;8(3):132-40
12045381
J Biol Chem. 2004 Mar 19;279(12):11244-52
14722101
Heart. 2007 Sep;93(9):1056-63
17395670
Brain Res. 2001 Feb 16;892(1):138-46
11172759
Toxicol Sci. 2004 May;79(1):75-81
14718647
Anal Biochem. 1976 May 7;72:248-54
942051
Circ Res. 1995 May;76(5):907-14
7729009
Antioxid Redox Signal. 2000 Spring;2(1):55-64
11232601
J Pharmacol Exp Ther. 1991 Oct;259(1):392-402
1920127
Crit Care Med. 2008 Jul;36(7):2106-16
18552690
Cardiology. 2010;115(4):243-50
20339300
Apoptosis. 2006 Nov;11(11):1887-97
16927020
Chembiochem. 2009 Jan 5;10(1):55-62
19089881
Birth Defects Res C Embryo Today. 2004 Dec;72(4):361-70
15662702
Arch Biochem Biophys. 2003 Dec 15;420(2):217-21
14654060
FASEB J. 2006 May;20(7):1024-6
16585059
Circulation. 2009 Apr 14;119(14):1941-9
19332462
Hypertension. 2003 Aug;42(2):206-12
12847113
Aging Cell. 2006 Apr;5(2):177-85
16626396