Contribution of Oxidative Stress and Inflammation to the Neurogenic Hypertension Induced by Intermittent Hypoxia

Oyarce, María P.; Iturriaga, Rodrigo

doi:10.3389/fphys.2018.00893

Cited by 30 publications

(30 citation statements)

References 79 publications

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“…There is a growing body of evidence suggesting that in addition to the neurotransmitters, immune signalling, as triggered by the activated innate immune system, can also modulate CB function (Fernandez et al., 2008; Kahlin et al., 2014; Lam et al., 2012; Liu, He, Stensaas, Dinger, & Fidone, 2009; Nardocci et al., 2015; Oyarce & Iturriaga, 2018). The initial immune response to various inflammogens, such as pathogen‐associated molecular patterns (PAMPs), results in mostly positive, regenerative effects; however, depending on the scale and duration of the inflammatory trigger, it may also develop into more detrimental hyperinflammatory conditions, i.e.…”

Section: Introductionmentioning

confidence: 99%

The impact of damage‐associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body

Mkrtchian

Kåhlin

Gómez-Galán

et al. 2020

Experimental Physiology

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New Findings What is the central question of this study?Are carotid bodies (CBs) modulated by the damage‐associated molecular patterns (DAMPs) and humoral factors of aseptic tissue injury? What are the main findings and their importance?DAMPs (HMGB1, S100 A8/A9) and blood plasma from rats subjected to tibia surgery, a model of aseptic injury, stimulate the release of neurotransmitters (ATP, dopamine) and TNF‐α from ex vivo rat CBs. All‐thiol HMGB1 mediates upregulation of immune‐related biological pathways. These data suggest regulation of CB function by endogenous mediators of innate immunity. Abstract The glomus cells of carotid bodies (CBs) are the primary sensors of arterial partial O2 and CO2 tensions and moreover serve as multimodal receptors responding also to other stimuli, such as pathogen‐associated molecular patterns (PAMPs) produced by acute infection. Modulation of CB function by excessive amounts of these immunomodulators is suggested to be associated with a detrimental hyperinflammatory state. We have hypothesized that yet another class of immunomodulators, endogenous danger‐associated molecular patterns (DAMPs), released upon aseptic tissue injury and recognized by the same pathogen recognition receptors as PAMPs, might modulate the CB activity in a fashion similar to PAMPs. We have tested this hypothesis by exposing rat CBs to various DAMPs, such as HMGB1 (all‐thiol and disulfide forms) and S100 A8/A9 in a series of ex vivo experiments that demonstrated the release of dopamine and ATP, neurotransmitters known to mediate CB homeostatic responses. We observed a similar response after incubating CBs with conditioned blood plasma obtained from the rats subjected to tibia surgery, a model of aseptic injury. In addition, we have investigated global gene expression in the rat CB using an RNA sequencing approach. Differential gene expression analysis showed all‐thiol HMGB1‐driven upregulation of a number of prominent pro‐inflammatory markers including Il1α and Il1β. Interestingly, conditioned plasma had a more profound effect on the CB transcriptome resulting in inhibition rather than activation of the immune‐related pathways. These data are the first to suggest potential modulation of CB function by endogenous mediators of innate immunity.

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Section: Introductionmentioning

confidence: 99%

The impact of damage‐associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body

Mkrtchian

Kåhlin

Gómez-Galán

et al. 2020

Experimental Physiology

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“…Well‐matched control samples are even more rare. Another major hurdle in understanding H/I‐induced molecular cascades is the complex milieu of secondary inflammatory mediators and cellular debris that accompany cell death (Oyarce & Iturriaga, ). These confounding factors make it difficult to ascertain whether such molecular events are secondary to hypoxia, subsequent inflammation, or both.…”

Section: Introductionmentioning

confidence: 99%

Galectin‐3 modulates postnatal subventricular zone gliogenesis

Al‐Dalahmah

Soares

Nicholson

et al. 2019

Glia

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Postnatal subventricular zone (SVZ) neural stem cells generate forebrain glia, namely astrocytes and oligodendrocytes. The cues necessary for this process are unclear, despite this phase of brain development being pivotal in forebrain gliogenesis. Galectin‐3 (Gal‐3) is increased in multiple brain pathologies and thereby regulates astrocyte proliferation and inflammation in injury. To study the function of Gal‐3 in inflammation and gliogenesis, we carried out functional studies in mouse. We overexpressed Gal‐3 with electroporation and using immunohistochemistry surprisingly found no inflammation in the healthy postnatal SVZ. This allowed investigation of inflammation‐independent effects of Gal‐3 on gliogenesis. Loss of Gal‐3 function via knockdown or conditional knockout reduced gliogenesis, whereas Gal‐3 overexpression increased it. Gal‐3 overexpression also increased the percentage of striatal astrocytes generated by the SVZ but decreased the percentage of oligodendrocytes. These novel findings were further elaborated with multiple analyses demonstrating that Gal‐3 binds to the bone morphogenetic protein receptor one alpha (BMPR1α) and increases bone morphogenetic protein (BMP) signaling. Conditional knockout of BMPR1α abolished the effect of Gal‐3 overexpression on gliogenesis. Gain‐of‐function of Gal‐3 is relevant in pathological conditions involving the human forebrain, which is particularly vulnerable to hypoxia/ischemia during perinatal gliogenesis. Hypoxic/ischemic injury induces astrogliosis, inflammation and cell death. We show that Gal‐3 immunoreactivity was increased in the perinatal human SVZ and striatum after hypoxia/ischemia. Our findings thus show a novel inflammation‐independent function for Gal‐3; it is necessary for gliogenesis and when increased in expression can induce astrogenesis via BMP signaling.

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“…This explains the enhanced sympathetic activity after glutamate injection in the cNTS in CIH-exposed rats compared with healthy rats (Costa-Silva et al, 2012). Other studies showed that exposure to CIH is associated with the upregulation of glutamatergic neurons in the NTS and increased expression of c-fos and fosB in the RVLM (Oyarce and Iturriaga, 2018). Therefore, increased peripheral afferent activity causes exaggerated central neural activity, which increases the production of ROS and cytokines in the NTS.…”

Section: Mechanisms Of Cih-induced Hypertensionmentioning

confidence: 98%

“…This induces microglial activation, which stimulates further increases in the levels of inflammatory cytokines. Exposure to CIH for 21 days caused an elevation of pro-inflammatory cytokines in the NTS and RVLM (Oyarce and Iturriaga, 2018). This hyperactivates NTS and PVN neurons, which increases renal sympathetic nerve activity and Ang II secretion.…”

Section: Mechanisms Of Cih-induced Hypertensionmentioning

confidence: 99%

Is Aberrant Reno-Renal Reflex Control of Blood Pressure a Contributor to Chronic Intermittent Hypoxia-Induced Hypertension?

2019

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Renal sensory nerves are important in the regulation of body fluid and electrolyte homeostasis, and blood pressure. Activation of renal mechanoreceptor afferents triggers a negative feedback reno-renal reflex that leads to the inhibition of sympathetic nervous outflow. Conversely, activation of renal chemoreceptor afferents elicits reflex sympathoexcitation. Dysregulation of reno-renal reflexes by suppression of the inhibitory reflex and/or activation of the excitatory reflex impairs blood pressure control, predisposing to hypertension. Obstructive sleep apnoea syndrome (OSAS) is causally related to hypertension. Renal denervation in patients with OSAS or in experimental models of chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoeas (pauses in breathing), results in a decrease in circulating norepinephrine levels and attenuation of hypertension. The mechanism of the beneficial effect of renal denervation on blood pressure control in models of CIH and OSAS is not fully understood, since renal denervation interrupts renal afferent signaling to the brain and sympathetic efferent signals to the kidneys. Herein, we consider the currently proposed mechanisms involved in the development of hypertension in CIH disease models with a focus on oxidative and inflammatory mediators in the kidneys and their potential influence on renal afferent control of blood pressure, with wider consideration of the evidence available from a variety of hypertension models. We draw focus to the potential contribution of aberrant renal afferent signaling in the development, maintenance and progression of high blood pressure, which may have relevance to CIH-induced hypertension.

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Contribution of Oxidative Stress and Inflammation to the Neurogenic Hypertension Induced by Intermittent Hypoxia

Cited by 30 publications

References 79 publications

The impact of damage‐associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body

The impact of damage‐associated molecular patterns on the neurotransmitter release and gene expression in the ex vivo rat carotid body

Galectin‐3 modulates postnatal subventricular zone gliogenesis

Is Aberrant Reno-Renal Reflex Control of Blood Pressure a Contributor to Chronic Intermittent Hypoxia-Induced Hypertension?

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