title: Cardiac-specific overexpression of metallothionein rescues against cigarette smoking exposure-induced myocardial contractile and mitochondrial damage.
abstract: OBJECTIVE
  Second 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 Ca(2+) properties and apoptosis following side-stream smoke exposure.
  
  
  METHODS
  Adult 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 Ca(2+) properties, fibrosis, apoptosis and mitochondrial damage were examined.
  
  
  RESULTS
  Our data revealed that smoke exposure enlarged ventricular end systolic and diastolic diameters, reduced myocardial and cardiomyocyte contractile function, disrupted intracellular Ca(2+) 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 Ca(2+) properties, the effect of which was mitigated by wortmannin and NAC.
  
  
  CONCLUSIONS
  These data suggest that side-stream smoke exposure led to myocardial dysfunction, intracellular Ca(2+) 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.
authors: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, Wyoming, United States of America.
authors: Nan
authors: N
authors: Hu
authors: Xuefeng
authors: X
authors: Han
authors: Erin K
authors: EK
authors: Lane
authors: Feng
authors: F
authors: Gao
authors: Yingmei
authors: Y
authors: Zhang
authors: Jun
authors: J
authors: Ren
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D005355:Fibrosis; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000473:pathology*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009928:Organ Specificity; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D000099211:Phospholamban
chemical_list: D000154:Aconitate Hydratase; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D002118:Calcium; D002135:Calcium-Binding Proteins; D045304:Cytochromes c; D008668:Metallothionein; D052250:Nitric Oxide Synthase Type III; D017382:Reactive Oxygen Species; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014028:Tobacco Smoke Pollution; D000099211:Phospholamban; C496315:Nos3 protein, mouse