Abstract
ObjectivesSecond hand cigarette smoke is an independent risk factor for cardiovascular disease. Although a tie between smoking and cardiovascular disease is well established, the underlying mechanisms still remains elusive due to the lack of adequate animal models. This study was designed to use a mouse model of exposure to cigarette smoke, a surrogate of environmental tobacco smoke, to evaluate the impact of cardiac overexpression of heavy metal scavenger metallothionein on myocardial geometry, contractile and intracellular Ca2+ properties and apoptosis following side-stream smoke exposure.MethodsAdult male wild-type FVB and metallothionein transgenic mice were placed in a chamber exposed to cigarette smoke for 1 hour daily for 40 days. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties, fibrosis, apoptosis and mitochondrial damage were examined.ResultsOur data revealed that smoke exposure enlarged ventricular end systolic and diastolic diameters, reduced myocardial and cardiomyocyte contractile function, disrupted intracellular Ca2+ homeostasis, facilitated fibrosis, apoptosis and mitochondrial damage (cytochrome C release and aconitase activity), the effects of which were attenuated or mitigated by metallothionein. In addition, side-stream smoke expose enhanced phosphorylation of Akt and GSK3β without affecting pan protein expression in the heart, the effect of which was abolished or ameliorated by metallothionein. Cigarette smoke extract interrupted cardiomyocyte contractile function and intracellular Ca2+ properties, the effect of which was mitigated by wortmannin and NAC.ConclusionsThese data suggest that side-stream smoke exposure led to myocardial dysfunction, intracellular Ca2+ mishandling, apoptosis, fibrosis and mitochondrial damage, indicating the therapeutic potential of antioxidant against in second smoking-induced cardiac defects possibly via mitochondrial damage and apoptosis.
Highlights
Chronic cigarette smoking predisposes individuals to various chronic diseases including cardiovascular diseases through overtly increased systemic oxidative stress 1]
Sidestream smoke exposure significantly reduced GSH levels and GSH/GSSG ratio without altering GSSG levels in hearts, the effect of which was alleviated by metallothionein
We further examined the effect of the smoke extract stream smoke extract (SSE) on cardiomyocyte function in vitro in the absence or presence of the antioxidant N-acetylcysteine (NAC, 500 mM), inhibitors for PI3K wortmannin (100 nM) and glycogen synthase kinase 3b (GSK3b) SB216763 (100 nM)
Summary
Chronic cigarette smoking predisposes individuals to various chronic diseases including cardiovascular diseases through overtly increased systemic oxidative stress 1]. Epidemiologic survey has indicated that cigarette smoking may increase the incidence of myocardial infarction and fatal coronary artery disease 2]. Even low-tar exposure of cigarette is known to drastically enhance the prevalence of cardiovascular diseases compared with non-smokers 2,3]. Passive smoking (second-hand smoking) may be associated with a 30% increase in the risk of coronary artery diseases compared with an 80% increase in activate smokers 2,4]. Given that smoking is a preventable global problem, a better understanding of how cigarette and second-hand smoking contribute to the pathogenesis of cardiovascular diseases is pivotal to the proper management of smoking-related premature death. While mice are widely employed in experimental medicine (such as smoking-induced lung diseases) and can offer a unique potential for genetic manipulation 5], few studies were performed with regards to the underlying mechanisms of cigarette smoking on cardiac function
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