title: Cigarette smoke increases cardiomyocyte ceramide accumulation and inhibits mitochondrial respiration.
abstract: BACKGROUND
  Cigarette smoking is a common and lethal worldwide habit, with considerable mortality stemming from its deleterious effects on heart function. While current theories posit altered blood lipids and fibrinogen metabolism as likely mediators, none have explored the role of the sphingolipid ceramide in exacerbating heart function with smoke exposure. Ceramide production is a consequence of cigarette smoke in the lung, and considering ceramide's harmful effects on mitochondrial function, we sought to elucidate the role of ceramide in mediating smoke-induced altered heart mitochondrial respiration.
  
  
  METHODS
  Lung cells (A549) were exposed to cigarette smoke extract (CSE) and heart cells (H9C2) were exposed to the lung-cell conditioned medium. Adult male mice were exposed sidestream cigarette smoke for 8 wk with dietary intervention and ceramide inhibition. Ceramides and heart cell or myocardial mitochondrial respiration were determined.
  
  
  RESULTS
  Lung cell cultures revealed a robust response to cigarette smoke extract in both production and secretion of ceramides. Heart cells incubated with lung-cell conditioned medium revealed a pronounced inhibition of myocardial mitochondrial respiration, though this effect was mitigated with ceramide inhibition via myriocin. In vivo, heart ceramides increased roughly 600% in adult mice with long-term sidestream cigarette smoke exposure. This resulted in a significant ceramide-dependent reduction in left myocardial mitochondrial respiration, as heart mitochondria from the mice exposed to both smoke and myriocin injections respired normally.
  
  
  CONCLUSIONS
  These results suggest ceramide to be an important mediator of altered myocardial mitochondrial function with cigarette smoke exposure. Thus, anti-ceramide therapies might be considered in the future to protect heart mitochondrial function with smoke exposure.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Tippetts
authors.forename: Duane R
authors.initials: DR
authors.lastname: Winden
authors.forename: Adam C
authors.initials: AC
authors.lastname: Swensen
authors.forename: Michael B
authors.initials: MB
authors.lastname: Nelson
authors.forename: Mikayla O
authors.initials: MO
authors.lastname: Thatcher
authors.forename: Rex R
authors.initials: RR
authors.lastname: Saito
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Condie
authors.forename: Kurtis J
authors.initials: KJ
authors.lastname: Simmons
authors.forename: Allan M
authors.initials: AM
authors.lastname: Judd
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
authors.affiliation: Department of Physiology and Developmental Biology and Chemistry, Brigham Young University, Provo, UT 84602, USA. benjamin_bikman@byu.edu.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002518:Ceramides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D002518:Ceramides; D017077:Culture Media, Conditioned; D005229:Fatty Acids, Monounsaturated; D012906:Smoke; C001996:thermozymocidin