A protective role of Nox1/NADPH oxidase in a mouse model with hypoxia-induced bradycardia

Kojima, Akiteru; Matsumoto, Akio; Nishida, Hitoshi; Reien, Yoshie; Iwata, Kazuo; Shirayama, Takeshi; Yabe‐Nishimura, Chihiro; Nakaya, Haruaki

doi:10.1016/j.jphs.2015.02.007

Cited by 10 publications

(5 citation statements)

References 24 publications

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“…Although both the loss of sinus rhythm during the clonic phase and the abrupt return of sinus rhythm during mechanical resuscitation closely coincide with respiratory changes, the pO2 and pCO2 are undoubtedly very different at these two points in time. Furthermore, several studies in mice have demonstrated that the initial response to hypoxia, ≤12% O 2 , is a reflex increase in heart rate followed by a decrease with no loss of P-wave over several minutes [16–19]. Hypercapnia (5%-6% CO 2 ) decreases heart rate, but does not eliminate SA nodal activity [19,20].…”

Section: Discussionmentioning

confidence: 99%

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP

et al. 2019

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This study was designed to evaluate cardiac and respiratory dysfunction in a mouse model of sudden unexpected death in epilepsy i.e., SUDEP. We simultaneously monitored respiration via plethysmography and the electrocardiogram via telemetry before, during, and after an audiogenic seizure. DBA/1 mice responded to an acoustic stimulus with one or two cycles of circling and jumping before entering a clonic/tonic seizure. This was followed by death unless the mice were resuscitated by mechanical ventilation using room air. During the initial clonic phase, respiration declined and cardiac rhythm is slowed. By the tonic phase, respiration had ceased, atrial P-waves were absent or dissociated from the QRS complex, and heart rate had decreased from 771±11 to 252±16 bpm. Heart rate further deteriorated terminating in asystole unless the mice were resuscitated at the end of the tonic phase which resulted in abrupt recovery of P-waves and a return to normal sinus rhythm, associated with gasping. Interestingly, P-waves were preserved in the mice treated with methylatropine during the pre-ictal period (to block parasympathetic stimulation) and heart rate remained unchanged through the end of the tonic phase (765±8 vs. 748±21 bpm), but as in control, methylatropine treated mice died from respiratory arrest. These results demonstrate that a clonic/tonic seizure in the DBA/1 mouse results in abrupt and simultaneous respiratory and cardiac depression. Although death clearly results from respiratory arrest, our results suggest that seizure activates two central nervous system pathways in this model—one inhibits respiratory drive, whereas the other inhibits cardiac function via vagal efferents. The abrupt and simultaneous recovery of both respiration and cardiac function with mechanical ventilation within an early post-ictal timeframe shows that the vagal discharge can be rapidly terminated. Understanding the central mechanism associated with the abrupt cardiorespiratory dysfunction and equally abrupt recovery may provide clues for therapeutic targets for SUDEP.

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Section: Discussionmentioning

confidence: 99%

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP

et al. 2019

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“…Besides the detrimental CVB3-induced inflammatory effect, also oxidative stress leads to an aggravation of myocardial injury [ 37 ] and thus exacerbates inflammation [ 38 ]. No changes were found in the expression of NOX1 and NOX4, which comprise two of the seven NADPH oxidases members [ 39 ] and are a major source of ROS [ 40 ]. However, iNOS and eNOS, the two main members of the NO family synthases [ 41 ], were differently expressed in CX3CR1 -/- CVB3 mice compared to WT CVB3 animals: whereas eNOS was downregulated in CX3CR1 -/- CVB3 versus WT CVB3 mice, iNOS expression was increased in those mice.…”

Section: Discussionmentioning

confidence: 99%

CX3CR1 knockout aggravates Coxsackievirus B3-induced myocarditis

et al. 2017

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Studies on inflammatory disorders elucidated the pivotal role of the CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with severe cardiac inflammation, which may progress to heart failure. We therefore investigated the influence of CX3CR1 ablation in the model of acute myocarditis, which was induced by inoculation with 5x105 plaque forming units of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days after infection, myocardial inflammation, remodeling, and titin expression and phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q diamond stain. Cardiac function was assessed by tip catheter. Compared to WT CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression of inflammatory cytokines and chemokines, which was associated with an increase of immune cell infiltration/presence. This shift towards a pro-inflammatory immune response further resulted in increased cardiac fibrosis and cardiomyocyte apoptosis, which was reflected by an impaired cardiac function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings demonstrate a cardioprotective role of CX3CR1 in CVB3-infected mice and indicate the relevance of the CX3CL1/CX3CR1 system in CVB3-induced myocarditis.

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“…However, NOX‐1 has also been reported to play a protective role against hypoxia‐induced SAN dysfunction. The recent report revealed that NOX‐1‐deficient (Nox1−/Y) mice are more sensitive to hypoxia and bradycardia than the WT mice, suggesting the physiological role of NOX‐1 in cardiac diseases 47 . Moreover, an elevated NOX‐2 expression and p47phox translocation was associated with increased activity of NOX enzymes, which resulted in elevated lipid peroxidation and the activation of ERK and JNK signalling leading to cell death after ischaemia‐reperfusion (I/R) 48 .…”

Section: Human Pathologies and Nox Connectionsmentioning

confidence: 99%

Molecular insights of NADPH oxidases and its pathological consequences

Waghela

Vaidya

Agrawal

et al. 2020

Cell Biochemistry & Function

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Reactive oxygen species (ROS), formed by the partial reduction of oxygen, were for a long time considered to be a byproduct of cellular metabolism. Since, increase in cellular levels of ROS results in oxidative stress leading to damage of nucleic acids, proteins, and lipids resulting in numerous pathological conditions; ROS was considered a bane for aerobic species. Hence, the discovery of NADPH oxidases (NOX), an enzyme family that specifically generates ROS as its prime product came as a surprise to redox biologists. NOX family proteins participate in various cellular functions including cell proliferation and differentiation, regulation of genes and protein expression, apoptosis, and host defence immunological response. Balanced expression and activation of NOX with subsequent production of ROS are critically important to regulate various genes and proteins to maintain homeostasis of the cell. However, dysregulation of NOX activation leading to enhanced ROS levels is associated with various pathophysiologies including diabetes, cardiovascular diseases, neurodegenerative diseases, ageing, atherosclerosis, and cancer. Although our current knowledge on NOX signifies its importance in the normal functioning of various cellular pathways; yet the choice of ROS producing enzymes which can tip the scale from homeostasis toward damage, as mediators of biological functions remain an oddity. Though the role of NOX in maintaining normal cellular functions is now deemed essential, yet its dysregulation leading to catastrophic events cannot be denied. Hence, this review focuses on the involvement of NOX enzymes in various pathological conditions imploring them as possible targets for therapies. Significance of the study The NOXs are multi‐subunit enzymes that generate ROS as a prime product. NOX generated ROS are usually regulated by various molecular factors and play a vital role in different physiological processes. The dysregulation of NOX activity is associated with pathological consequences. Recently, the dynamic proximity of NOX enzymes with different molecular signatures of pathologies has been studied extensively. It is essential to identify the precise role of NOX machinery in its niche during the progression of pathology. Although inhibition of NOX could be a promising approach for therapeutic interventions, it is critical to expand the current understanding of NOX's dynamicity and shed light on their molecular partners and regulators.

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A protective role of Nox1/NADPH oxidase in a mouse model with hypoxia-induced bradycardia

Cited by 10 publications

References 24 publications

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP

CX3CR1 knockout aggravates Coxsackievirus B3-induced myocarditis

Molecular insights of NADPH oxidases and its pathological consequences

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