Smoking And Nicotine Induced Cardiac Failure And Protection Of Metallothionein On Mice Heart

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 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 H&E and Masson trichrome staining, respectively. Oxidative stress and apoptosis were measured by 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 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.Second hand cigarette smoke is deemed an independent risk factor for cardiovascular disease. Although the association between chronic smoking and cardiovascular disease is well established, the underlying mechanisms are still poorly understood due to the lack of adequate in vivo animal models. Thus 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-specific overexpression of heavy metal scavenger metallothionein on myocardial geometry, contractile and intracellular Ca2+ properties and apoptosis following side-stream smoke exposure. Adult male wild-type FVB and metallothionein transgenic mice were placed in a cage exposed to 1 cigarette's smoke for 1 hr/day for 40 days. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties, apoptosis and mitochondrial damage were examined. Our data revealed that smoke exposure significantly enlarged ventricular end systolic and end diastolic diameters, reduced myocardial and cardiomyocyte contractile function, disrupted intracellular Ca2+ homeostasis, provoked apoptosis and mitochondrial damage (cytochrome C release and reduced aconitase activity), the effects of which were attenuated or mitigated by metallothionein. In addition, side-stream smoke exposed mice displayed enhanced phosphorylation of Akt and GSK3βwithout affecting pan protein expression in the heart, the effect of which was abolished or ameliorated by metallothionein. Taken together, these data suggest that side-stream smoke exposure led to myocardial contractile dysfunction, intracellular Ca2+ mishandling, apoptosis and mitochondrial damage, indicating the therapeutic potential of antioxidant against in side-stream smoking-induced cardiac defects possibly via mitochondrial damage and apoptosis.