title: Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner.
abstract: Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function.
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Nelson
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Swensen
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Duane R
authors.initials: DR
authors.lastname: Winden
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Jared S
authors.initials: JS
authors.lastname: Bodine
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and paul_reynolds@byu.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D019069:Cell Respiration; D002518:Ceramides / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014028:Tobacco Smoke Pollution
chemical_list: D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014028:Tobacco Smoke Pollution; C048496:N(6)-carboxymethyllysine; D008239:Lysine; C001996:thermozymocidin
keywords: cardiomyopathy; ceramide; cigarette smoke; mitochondria; receptor for advanced glycation end products