The online version of this article (doi:10.1186/1471-2261-14-165) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
TST, MBN, MOT, RRS, TBC, KJS conducted cell culture studies. TST, DRW, MBN, MOT, RRS, TBC, KJS performed animal studies. TST, ACS, MOT isolated and quantified ceramides. TST, BTB performed mitochondrial assays. PRR provided technical expertise with sidestream cigarette smoke studies. AMJ, BTB conceived of the study. BTB prepared the manuscript. All authors read and approved the final manuscript.
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.
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.
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.
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.
WHO urges more countries to require large, graphic health warnings on tobacco packaging: the WHO report on the global tobacco epidemic, 2011 examines anti-tobacco mass-media campaigns. Cent Eur J Public Health. 2011, 19: 133-151.
Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings. Substance Abuse and Mental Health Services Administration. 2011
Vital signs: nonsmokers' exposure to secondhand smoke - United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 2010, 59: 1141-1146.
Smoking-attributable mortality, years of potential life lost, and productivity losses--United States, 2000-2004. MMWR Morb Mortal Wkly Rep. 2008, 57: 1226-1228.
Reynolds PR, Schmitt RE, Kasteler SD, Sturrock A, Sanders K, Bierhaus A, Nawroth PP, Paine R, Hoidal JR: Receptors for advanced glycation end-products targeting protect against hyperoxia-induced lung injury in mice. Am J Respir Cell Mol Biol. 2010, 42: 545-551. 10.1165/rcmb.2008-0265OC. CrossRefPubMed
Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti MJ, Scherer PE, Summers SA: Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest. 2011, 121: 1858-1870. 10.1172/JCI43378. CrossRefPubMedPubMedCentral
Baranowski M, Blachnio A, Zabielski P, Gorski J: PPARalpha agonist induces the accumulation of ceramide in the heart of rats fed high-fat diet. J Physiol Pharmacol. 2007, 58: 57-72. PubMed
Lough J: Cardiomyopathy produced by cigarette smoke. Ultrastructural observations in guinea pigs. Arch Pathol Lab Med. 1978, 102: 377-380. PubMed
Thatcher MO, Tippetts TS, Nelson MB, Swensen AC, Winden DR, Hansen ME, Anderson MC, Johnson IE, Porter JP, Prince JT, Reynolds PR, Bikman BT: Ceramides mediate cigarette smoke-induced metabolic disruption in mice. Am J Physiol Endocrinol Metab. 2014
Schweitzer KS, Hatoum H, Brown MB, Gupta M, Justice MJ, Beteck B, Van Demark M, Gu Y, Presson RG, Hubbard WC, Petrache I: Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides. Am J Physiol Lung Cell Mol Physiol. 2011, 301: L836-846. 10.1152/ajplung.00385.2010. CrossRefPubMedPubMedCentral
- Cigarette smoke increases cardiomyocyte ceramide accumulation and inhibits mitochondrial respiration
Trevor S Tippetts
Duane R Winden
Adam C Swensen
Michael B Nelson
Mikayla O Thatcher
Rex R Saito
Tyler B Condie
Kurtis J Simmons
Allan M Judd
Paul R Reynolds
Benjamin T Bikman
- BioMed Central
Neu im Fachgebiet Kardiologie
Mail Icon II