NADPH Oxidase 2 Mediates Intermittent Hypoxia-Induced Mitochondrial Complex I Inhibition: Relevance to Blood Pressure Changes in Rats

Khan, Shakil A.; Nanduri, Jayasri; Yuan, Guoxiang; Kinsman, Brian; Kumar, Ganesh K.; Joseph, Joy; Kalyanaraman, Balaraman; Prabhakar, Nanduri R.

doi:10.1089/ars.2010.3213

Cited by 78 publications

(81 citation statements)

References 45 publications

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“…The decreased Sod2 mRNA was associated with reduced MnSOD activity and elevated ROS levels in the mitochondria. Previous studies have shown that ROS are potent inhibitors of complex I activity (19,20). Indeed, we found reduced activity of complex I, but not complex III, in Hif-2α +/− mice.…”

Section: Breathing (Mean ± Sem) (G-j) Mean (Mbp) Systolic (Sbp) Ansupporting

confidence: 52%

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Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension

Peng

Nanduri

Khan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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103

123

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Cardiorespiratory functions in mammals are exquisitely sensitive to changes in arterial O 2 levels. Hypoxia-inducible factors (e.g., HIF-1 and HIF-2) mediate transcriptional responses to reduced oxygen availability. We demonstrate that haploinsufficiency for the O 2 -regulated HIF-2α subunit results in augmented carotid body sensitivity to hypoxia, irregular breathing, apneas, hypertension, and elevated plasma norepinephrine levels in adult Hif-2α +/− mice. These dysregulated autonomic responses were associated with increased oxidative stress and decreased mitochondrial electron transport chain complex I activity in adrenal medullae as a result of decreased expression of major cytosolic and mitochondrial antioxidant enzymes. Systemic administration of a membrane-permeable antioxidant prevented oxidative stress, normalized hypoxic sensitivity of the carotid body, and restored autonomic functions in Hif-2α +/− mice. Thus, HIF-2α-dependent redox regulation is required for maintenance of carotid body function and cardiorespiratory homeostasis.blood pressure | control of ventilation | catecholamines H ypoxia-inducible factors (HIFs) mediate transcriptional responses to reduced O 2 availability (1). HIF-1, the first identified member of the HIF family, is comprised of an O 2 -regulated α subunit and a constitutively expressed β subunit (2). Complete deficiency of HIF-1α in Hif-1α −/− mice results in embryonic lethality at midgestation with major malformations of the central nervous system, heart, and vasculature (3). Hif-1α +/− mice, which are partially deficient in HIF-1α expression, develop normally and are indistinguishable from their WT littermates in the sedentary state with respect to autonomic functions, including blood pressure (BP), ventilatory responses to hypoxia or hypercapnia, and plasma catecholamine levels (4). However, Hif-1α +/− mice exhibit impaired O 2 sensing by the carotid body (4, 5), the primary sensory organ for detecting hypoxemia (6, 7), and altered physiological adaptations to chronic hypoxia (5, 8).The HIF-2α subunit, also known as endothelial PAS domain protein-1 (EPAS-1), shares 48% amino acid sequence identity with HIF-1α (9). As in the case of HIF-1α, continuous hypoxia leads to HIF-2α accumulation and subsequent dimerization with HIF-1β. Transcriptional activation by HIF-2 regulates some target genes in common with HIF-1 as well as other genes that are uniquely regulated by HIF-2 (10-12). Homozygous deficiency of HIF-2α is often lethal with the surviving Hif-2α -/− mice exhibiting multiple organ pathology and increased oxidative stress as a result of impaired induction of genes encoding major antioxidant enzymes (AOEs) (12).Hif-2α +/− mice, like Hif-1α +/− mice, are phenotypically indistinguishable from WT littermates under sedentary conditions, but exhibit impaired responses to chronic hypoxia such as impaired pulmonary vascular remodeling, erythropoiesis, and retinal neovascularization (13-15). Although the carotid body is a prominent site of HIF-2α expression (16), the effects of Hi...

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Section: Breathing (Mean ± Sem) (G-j) Mean (Mbp) Systolic (Sbp) Ansupporting

confidence: 52%

“…3 E and F), a sensitive biomarker of ROS (18). Mitochondrial electron transport chain (ETC) complex I activity, which is also a target for ROS (19,20), was significantly decreased in Hif-2α +/− mice, whereas ETC complex III activity was unaffected (Fig. 3G).…”

Section: Resultsmentioning

confidence: 97%

Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension

Peng

Nanduri

Khan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

123

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“…Outside of the mitochondrion, oxygen can be consumed in the generation of reactive oxygen species and NO by NADPH oxidase and NOS, respectively. 17,18 Because reactive oxygen species and NO have been reported to inhibit mitochondrial function in other systems, 19,20 we investigated whether these processes could also play a role in this situation. Although NAPDH oxidase was functionally expressed in BM-derived DCs 21 ( Figure 2A), specific inhibition of this enzyme complex had no effect on nonmitochondrial oxygen consumption ( Figure 2B), suggesting that this enzyme is not active and does not play a role in impairment of mitochondrial function in these cells.…”

Section: Tlr-driven Impairment Of Mitochondrial Respiration In Dcs Ismentioning

confidence: 99%

Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

Everts

Amiel

Windt

et al. 2012

Blood

473

568

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TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte-derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte-derived DCs. (Blood. 2012;120(7):1422-1431) IntroductionDendritic cells (DCs) express TLRs that allow them to detect and respond to pathogen-derived molecules. 1,2 In response to TLR agonists, DCs transition from a resting state to an activated state through a process that that involves the induction of expression of genes encoding a broad array of proteins such as cytokines, chemokines, and costimulatory molecules. 3 Activated DCs play a central role in orchestrating the development of immune responses.Recently, we showed that after exposure to TLR agonists, DCs undergo a striking metabolic transition evident as a pronounced increase in the glycolytic rate. 4 This is highly reminiscent of Warburg metabolism, 5 in which tumor cells preferentially use glycolysis rather than catabolic mitochondrial pathways to conserve and generate metabolic resources to meet the demands of cellular proliferation while still producing sufficient ATP to permit these processes to occur. 6,7 Moreover, the increase in glycolytic rate in DCs was found to be dependent on the PI3K/Akt pathway, 4 which is one of the most commonly mutated signaling pathways in tumors. 8 We reasoned that glycolysis could serve essentially the same purpose in active DCs as it is thought to do in tumors. 4 This view was supported by the fact that glucose restriction inhibits severely the activation and life span of DCs exposed to TLR agonists. 4 However, unlike in most cancers, which continue to consume oxygen at rates comparable to normal tissues despite increased glycolytic rates, 9 activated DCs use significantly less oxygen than do resting DCs. 4 Thus far, the molecular mechanisms underlying mitochondrial impairment in activated DCs, and the metabolic consequences of the loss of mitochondrial function, remain unclear.To address these issues, we have in the present study, undertaken a detailed analysis of mitochondrial function in DCs after TLR stimulation. Using extracellular flux analysis to measure changes in oxygen consumption in real time, we found that 6 hours after stimulation, mitochondrial oxygen consumption was progressively lost due to the ...

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“…Such activation leads to hyperpolarization of the plasma membrane, decreased excitability, and lowered metabolic demands (14,223,258). Direct evidence for IH-induced activation of K ATP channels in brain is lacking; however, events leading to neuronal K ATP activation, including ROS production, NO-induced protein kinase G (PKG) signaling, mitochondrial K ATP activation and activation of CaMK (32, 33, 115, 243) were observed to occur in brain following IH exposure (115,243).…”

Section: Central Nervous Systemmentioning

confidence: 99%

Hypoxia. 4. Hypoxia and ion channel function

Shimoda

Polàk

2011

American Journal of Physiology-Cell Physiology

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The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes. oxygen deprivation; mammalian ion channels; oxygen homeostasis SENSING and appropriately responding to changes in O 2 concentration is of paramount importance for the survival of all organisms. Over time, O 2 homeostasis has evolved into a complex system to regulate O 2 delivery and use. While the rapid response to acute reductions in O 2 concentration typically results from processes that alter preexisting proteins, such as phosphorylation, stabilization, dimerization, or degradation, durable adaptation to prolonged hypoxic insult requires a coordinated response at the level of gene transcription. Since a deficit in O 2 is an important component of various physiological processes and the pathogenesis of numerous diseases, understanding the mechanisms by which changes in O 2 are linked to cell function is of great interest.Ion channels play a critical role in regulating a wide variety of biological processes, including neuronal transmission; control of ventillation; contraction of cardiac, skeletal, and smooth muscle; transport of nutrients and ions across the epithelium; T-cell activation; and glucose metabolism and pancreatic ␤-cell insulin release. To date, over 300 types of ion channels, differing in their mode of activation (voltage-dependent or -independent, ligand-gated, mechanosensitive, pH) and their ionic permeability (K ϩ , Ca 2ϩ , Cl Ϫ , Na ϩ ), have been identified. This heterogeneity in ion channel populations provides an astonishing array of variable responses within and between cell types. In 1988, a report demonstrating that rabbit carotid body glomus cells express an O 2 -sensitive potassium channel ushered in a new era of research exploring whether ion channel activity could be regulated in response to changes in O 2 availability (131). Since that initial description of an O 2 -regulated ion channel, an abundance of work has been produced indicating that a variety of ion channels spread across the different ion channel families are O 2 sensitive and exhibit changes in channel activity with acute hypoxia and alterations in channel quantity with prolonged hypoxic challenge. Although a great amount of work has been devoted to the study of hypoxia and ion channels in reptiles, amp...

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NADPH Oxidase 2 Mediates Intermittent Hypoxia-Induced Mitochondrial Complex I Inhibition: Relevance to Blood Pressure Changes in Rats

Cited by 78 publications

References 45 publications

Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension

Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension

Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells

Hypoxia. 4. Hypoxia and ion channel function

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