title: The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome.
abstract: The metabolic syndrome is associated with prolonged stress and hyperactivity of the sympathetic nervous system and afflicted subjects are prone to develop cardiovascular disease. Under normal conditions, the cardiomyocyte response to acute β-adrenergic stimulation partly depends on increased production of reactive oxygen species (ROS). Here we investigated the interplay between beta-adrenergic signaling, ROS and cardiac contractility using freshly isolated cardiomyocytes and whole hearts from two mouse models with the metabolic syndrome (high-fat diet and ob/ob mice). We hypothesized that cardiomyocytes of mice with the metabolic syndrome would experience excessive ROS levels that trigger cellular dysfunctions. Fluorescent dyes and confocal microscopy were used to assess mitochondrial ROS production, cellular Ca2+ handling and contractile function in freshly isolated adult cardiomyocytes. Immunofluorescence, western blot and enzyme assay were used to study protein biochemistry. Unexpectedly, our results point towards decreased cardiac ROS signaling in a stable, chronic phase of the metabolic syndrome because: β-adrenergic-induced increases in the amplitude of intracellular Ca2+ signals were insensitive to antioxidant treatment; mitochondrial ROS production showed decreased basal rate and smaller response to β-adrenergic stimulation. Moreover, control hearts and hearts with the metabolic syndrome showed similar basal levels of ROS-mediated protein modification, but only control hearts showed increases after β-adrenergic stimulation. In conclusion, in contrast to the situation in control hearts, the cardiomyocyte response to acute β-adrenergic stimulation does not involve increased mitochondrial ROS production in a stable, chronic phase of the metabolic syndrome. This can be seen as a beneficial adaptation to prevent excessive ROS levels.
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Monica
authors.initials: M
authors.lastname: Llano-Diez
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Jon
authors.initials: J
authors.lastname: Sinclair
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Karolinska University Hospital, Rheumatology unit, CMM, Stockholm Sweden.
authors.forename: Mei
authors.initials: M
authors.lastname: Zong
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fauconnier
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Shi-Jin
authors.initials: SJ
authors.lastname: Zhang
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Jardemark
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
authors.affiliation: Karolinska Institutet, Department of Medicine, Stockholm, Sweden.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.affiliation: Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden.
authors.forename: Johanna T
authors.identifier: http://orcid.org/0000-0002-1222-9473
authors.initials: JT
authors.lastname: Lanner
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004558:Electric Stimulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000318:Adrenergic beta-Agonists; D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D006861:Hydrogen Peroxide; D007545:Isoproterenol; D002118:Calcium