title: Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy.
abstract: Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.
authors.affiliation: Department of Circulation and Medical Imaging, Faculty of Medicine, The Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Anja
authors.initials: A
authors.lastname: Bye
authors.forename: Sveinung
authors.initials: S
authors.lastname: Sørhaug
authors.forename: Marcello
authors.initials: M
authors.lastname: Ceci
authors.forename: Morten A
authors.initials: MA
authors.lastname: Høydal
authors.forename: Tomas
authors.initials: T
authors.lastname: Stølen
authors.forename: Garrett
authors.initials: G
authors.lastname: Heinrich
authors.forename: Arnt E
authors.initials: AE
authors.lastname: Tjønna
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Odd G
authors.initials: OG
authors.lastname: Nilsen
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: Serena
authors.initials: S
authors.lastname: Grimaldi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Contu
authors.forename: Sigurd
authors.initials: S
authors.lastname: Steinshamn
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Oyvind
authors.initials: O
authors.lastname: Ellingsen
authors.forename: Helge
authors.initials: H
authors.lastname: Waldum
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisløff
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000502:physiology; D002248:Carbon Monoxide / Q000633:toxicity*; D006332:Cardiomegaly / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D002248:Carbon Monoxide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D006152:Cyclic GMP; D010100:Oxygen; D002118:Calcium