Insulin-dependent metabolic and inotropic responses in the heart are modulated by hydrogen peroxide from NADPH-oxidase isoforms NOX2 and NOX4

Hydrogen peroxide (H2O2) is a stable reactive oxygen species (ROS) that has long been implicated in insulin signal transduction in adipocytes. However, H2O2's role in mediating insulin's effects on the heart are unknown. We investigated the role of H2O2 in activating insulin-dependent chan...

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Published in:Free radical biology & medicine 2017-12, Vol.113, p.16-25
Main Authors: Steinhorn, Benjamin, Sartoretto, Juliano L., Sorrentino, Andrea, Romero, Natalia, Kalwa, Hermann, Abel, E. Dale, Michel, Thomas
Format: Article
Language:English
Subjects:
Animals
Diabetes Mellitus, Type 2 - enzymology
Diabetes Mellitus, Type 2 - metabolism
Disease Models, Animal
Fluorescent biosensors
Hydrogen Peroxide - metabolism
Insulin
Insulin - metabolism
Mice
Myocytes, Cardiac - enzymology
Myocytes, Cardiac - metabolism
NADPH Oxidase 2 - metabolism
NADPH Oxidase 4 - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Reactive Oxygen Species - metabolism
Redox signaling
Signal Transduction
TOR Serine-Threonine Kinases - metabolism
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Summary:Hydrogen peroxide (H2O2) is a stable reactive oxygen species (ROS) that has long been implicated in insulin signal transduction in adipocytes. However, H2O2's role in mediating insulin's effects on the heart are unknown. We investigated the role of H2O2 in activating insulin-dependent changes in cardiac myocyte metabolic and inotropic pathways. The sources of insulin-dependent H2O2 generation were also studied. In addition to the canonical role of insulin in modulating cardiac metabolic pathways, we found that insulin also inhibited beta adrenergic-induced increases in cardiac contractility. Catalase and NADPH oxidase (NOX) inhibitors blunted activation of insulin-responsive kinases Akt and mTOR and attenuated beta adrenergic receptor-mediated responses. These insulin responses were lost in a mouse model of type 2 diabetes, suggesting a role for these H2O2-dependent pathways in the diabetic heart. The H2O2-sensitive fluorescent biosensor HyPer revealed rapid increases in cytosolic and caveolar H2O2 concentrations in response to insulin treatment, which were blocked by NOX inhibitors and attenuated in NOX2 KO and NOX4 KO mice. In NOX2 KO cardiac myocytes, insulin-mediated phosphorylation of Akt and mTOR was blocked, while these responses were unaffected in cardiac myocytes from NOX4 KO mice. In contrast, insulin's effects on contractility were lost in cardiac myocytes from NOX4 KO animals but were retained in NOX2 KO mice. These studies identify a proximal point of bifurcation in cardiac insulin signaling through the simultaneous activation of both NOX2 and NOX4. Each NOX isoform generates H2O2 in cardiac myocytes with distinct time courses, with H2O2 derived from NOX2 augmenting Akt-dependent metabolic effects of insulin, while H2O2 from NOX4 blocks beta adrenergic increases in inotropy. These findings suggest that insulin resistance in the diabetic heart may lead to potentially deleterious potentiation of beta adrenergic responses. [Display omitted] •Insulin signaling in cardiac myocytes is modulated by H2O2 from Nox2 and Nox4.•Nox2 couples insulin to “canonical” insulin-modulated phosphorylation pathways.•In contrast, Nox4 modulates insulin-dependent attenuation of β-adrenergic pathways.•Insulin has a “beta blocker-like” effect on cardiac physiological responses.•Insulin/H2O2–mediated responses are lost in an animal model of Type II diabetes.•Insulin-modulated oxidant pathways may be important in diabetic cardiomyopathy.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2017.09.006