The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome

• Published in: PloS one Vol. 11; no. 12; p. e0167090
• Main Authors: Llano-Diez, Monica, Sinclair, Jon, Yamada, Takashi, Zong, Mei, Fauconnier, Jeremy, Zhang, Shi-Jin, Katz, Abram, Jardemark, Kent, Westerblad, Håkan, Andersson, Daniel C., Lanner, Johanna T.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2016; Public Library of Science (PLoS)
• Subjects: Adrenergic beta-Agonists - pharmacology; Adrenergic transmission; Animal models; Animals; Antioxidants; Biochemistry; Biochemistry, Molecular Biology; Biology and Life Sciences; Calcium (intracellular); Calcium (mitochondrial); Calcium - metabolism; Calcium signalling; Cardiology and cardiovascular system; Cardiomyocytes; Cardiomyopathies - etiology; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiovascular diseases; Cellular manufacture; Confocal microscopy; Diabetes; Diet; Diet, High-Fat - adverse effects; Electric Stimulation; Experiments; Fluorescence; Fluorescent dyes; Fluorescent indicators; Gene expression; Health sciences; Heart; Heart diseases; Heart failure; High fat diet; Human health and pathology; Hydrogen Peroxide - pharmacology; Hyperactivity; Immunofluorescence; Insulin resistance; Isoproterenol - pharmacology; Kinases; Life Sciences; Male; Medicine and Health Sciences; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - etiology; Metabolic Syndrome - metabolism; Metabolic Syndrome - pathology; Mice; Mice, Inbred C57BL; Microscopy; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Muscle contraction; Musculoskeletal system; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nervous system; Obesity - etiology; Obesity - metabolism; Obesity - pathology; Organ Culture Techniques; Oxidative stress; Oxygen; Pharmacology; Physiology; Primary Cell Culture; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Adrenergic, beta - metabolism; Research and Analysis Methods; Rodents; Signal Transduction; Stimulation; Sympathetic nervous system; Denmark; Sweden
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167090

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.