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A protective role of Nox1/NADPH oxidase in a mouse model with hypoxia-induced bradycardia
Akiteru Kojima1, Akio Matsumoto2, Hirofumi Nishida2
1Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Abstract:
Although it has been reported that endotoxin-induced expression of Nox1 in the heart contributes to apoptosis in cardiomyocytes, functional role of Nox1 at the physiological expression level has not been elucidated. The aim of this study was to clarify the role of Nox1 under a hypoxic condition using wild-type (WT, Nox1(+/Y)) and Nox1-deficient (Nox1(-/Y)) mice. ECG recordings from anesthetized mice revealed that Nox1(-/Y) mice were more sensitive to hypoxia, resulting in bradycardia, compared to WT mice. Atrial and ventricular electrocardiograms recorded from Langendorff-perfused hearts revealed that hypoxic perfusion more rapidly decreased heart rate in Nox1(-/Y) hearts compared with WT hearts. Sinus node recovery times measured under a hypoxic condition were prolonged more markedly in the Nox1(-/Y) hearts. Sinoatrial node dysfunction of Nox1(-/Y) hearts during hypoxia was ameriolated by the pre-treatment with the Ca(2+) channel blocker nifedipine or the K(+) channel opener pinacidil. Spontaneous action potentials were recorded from enzymatically-isolated sinoatrial node (SAN) cells under a hypoxic condition. There was no significant difference in the elapsed times from the commencement of hypoxia to asystole between WT and Nox1(-/Y) SAN cells. These findings suggest that Nox1 may have a protective effect against hypoxia-induced SAN dysfunction.
Insights
Mice lacking Nox1 (Nicotinamide adenine dinucleotide phosphate oxidase 1) showed increased sensitivity to hypoxia, leading to more severe bradycardia and sinoatrial node dysfunction. These findings suggest Nox1 plays a protective role against hypoxia-induced heart problems.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Oxidative Stress
Background:
- Endotoxin-induced Nox1 expression in the heart is linked to cardiomyocyte apoptosis.
- The physiological role of Nox1 at normal expression levels, particularly during hypoxia, remains unclear.
Purpose of the Study:
- To investigate the functional role of Nox1 under hypoxic conditions using wild-type and Nox1-deficient mice.
- To elucidate the protective mechanisms of Nox1 against hypoxia-induced sinoatrial node dysfunction.
Main Methods:
- Electrocardiogram (ECG) recordings in anesthetized and Langendorff-perfused mice.
- Measurement of sinus node recovery times under hypoxic conditions.
- Recording of spontaneous action potentials from isolated sinoatrial node cells.
Main Results:
- Nox1-deficient mice exhibited increased sensitivity to hypoxia, manifesting as more pronounced bradycardia compared to wild-type mice.
- Hypoxic perfusion led to a faster decrease in heart rate in Nox1-deficient hearts.
- Hypoxia-induced sinoatrial node dysfunction was exacerbated in Nox1-deficient hearts, but ameliorated by nifedipine or pinacidil treatment.
Conclusions:
- Nox1 appears to have a protective effect against hypoxia-induced sinoatrial node dysfunction.
- Nox1 deficiency exacerbates cardiac sensitivity to hypoxia, impacting heart rate regulation.
- Further research is warranted to fully understand Nox1's role in cardiac homeostasis during stress.
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