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.

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

“…When antioxidant apocynin was provided in the drinking water, appearance of ventricular arrhythmias in this model was completely abolished. Interestingly, results from Fauconnier et al (2007) and Llano-Diez et al (2016) suggest that in ob/ob and HFD mice at certain stages of disease development, mitochondrial ROS emission is reduced. Fauconnier et al (2007) proposed that during prolonged exposure to increased fatty acid levels due to the switch in mitochondrial substrate utilization, cardiomyocytes from the ob/ob mouse adapt to preferential use of fatty acids for metabolism, so further exposure to fatty acids improved intracellular Ca 2+ homeostasis in this model.…”

Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart

“…It’s noteworthy that short-term HFD feeding leads to decreases in cardiac functional reserve and mitochondrial ROS production in response to β-adrenergic stimulation without significant alteration in β 1 AR and β 2 AR expression, cardiac structure, and cardiac function [34, 35]. This decrease in cardiac functional reserve is associated with significant increases in the levels of phosphorylation of β 2 AR at PKA and GRK sites.…”

“…The fragmented mitochondria usually lead to less effective respiratory chain reaction [72]. Thus, acute β-adrenergic stimulation increases the production of ROS[35]; and transgenic activation of βAR leads to an elevation of NADPH oxidase activity with greater ROS production [73]. Meanwhile, cardiac glycogen utility involves a complex interplay between multiple signaling pathways including insulin-dependent glycogen synthesis [74], βAR-dependent glycogen breakdown [75], and AMPK [76].…”

Risk assessment of cardiotoxicity to zebrafish (Danio rerio) by environmental exposure to triclosan and its derivatives

“…Early-state metabolic syndrome may enhance badrenergic stimulation and trigger production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. Increased ROS production may result in severe pathological changes and contribute to cardiac dysfunction (Llano-Diez et al, 2016). Importantly, changes in SOD activity control the level of ROS (Wang et al, 2018).…”