Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction

Dunham‐Snary, Kimberly J.; Wu, Danchen; Potus, François; Sykes, Edward A.; Mewburn, Jeffrey; Charles, Rebecca L.; Eaton, Philip; Sultanian, Richard; Archer, Stephen L.

doi:10.1161/circresaha.118.314284

Cited by 72 publications

(47 citation statements)

References 60 publications

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“…Some patients experience decompensation due to respiratory failure hypoxemia, and often without warning. This condition is caused by diffuse alveolar damage, alveolar uid accumulation, and occasional hyaline membrane disease, leading to ARDS [6].…”

Section: Discussionmentioning

confidence: 99%

Possible silent hypoxemia in a COVID-19 patient: a case report

Siswanto

Gani

Fauzi

et al. 2020

Preprint

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Background: It has been hypothesized that silent hypoxemia is the cause of the rapid progressive respiratory failure with severe hypoxia that occurs in some patients with COVID-19 without warning. Here, we reported one COVID-19 case with the possibility of silent hypoxemia. Case presentation: A 60-year-old male presented with complaints of cough that he felt starting two weeks before admission without any breathing difficulty. Complaints were accompanied by fever, runny nose and sore throat. Vital signs examination showed blood pressure 130/75 mmHg, pulse 84 times per minute, normal respiratory rate (RR) of 21 times per minute, body temperature 36.5 C, and 99% oxygen saturation with oxygen via nasal cannula 3 liters per minute were recorded. On physical examination, an increase in vesicular sounds and crackles in both lungs were identified. Chest x-ray showed bilateral pneumonia. Nasopharyngeal and oropharyngeal swab real-time polymerase chain reaction tests for COVID-19 were positive. On the third day of treatment, the patient complained of worsening of shortness of breath, but his RR was still normal with 22 times per minute. On the fifth day of treatment, the patient experienced severe shortness of breath with a RR of 38 times per minute. The patient was then intubated and his blood gas analysis showed respiratory alkalosis (pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1 mmHg, HCO3 26.9 mEq/L, SaO2 94.7%). On the eighth day of treatment, his condition deteriorated starting in the morning, with blood pressure 80/40 mmHg with norepinephrine support, pulse 109 times per minute, and 72% SpO2 with ventilator. In the afternoon, the patient experienced cardiac arrest and underwent basic life support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis showed severe respiratory acidosis (pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1 mEq /L, SaO2 78.7%). Three hours later, he suffered cardiac arrest again, but was unable to be resuscitated. The patient eventually died.Conclusions: Silent hypoxemia might be considered as an early clinical sign of deterioration of patients with COVID-19, thus, the physician may be able to intervene early and decrease its morbidity and mortality.

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Section: Discussionmentioning

confidence: 99%

Possible silent hypoxemia in a COVID-19 patient: a case report

Siswanto

Gani

Fauzi

et al. 2020

Preprint

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“…Among them, the up-regulation of EPHX2 is related to endoplasmic reticulum stress in obesity, physical activity may reduce metabolic stress by inhibiting EPHX2 expression, and then activating PI3K/Akt/GSK3 β signal pathway to achieve the protective effect of antioxidant injury [17,18]. Down-regulated proteins include Ndufs2, PNPO, CST3, AXL, NDUFA4L2, NDUFS6, MFGE8 and SUMO3, in which Ndufs2 is the core subunit of mitochondrial complex I, which can improve pulmonary vascular sensitivity during acute hypoxia and play an important protective role in hypoxic pulmonary vasoconstriction [19]. It has been reported that CST3 has protective effects on various oxidative stress injuries that induce neuronal apoptosis [20].…”

Section: Discussionmentioning

confidence: 99%

Expression of NAD(P)H:Quinone Oxidoreductase 1 and Its Significance in Human Abdominal Aortic Aneurysmal Tissues

Zhang

Zhao

Xiong

et al. 2020

Preprint

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Background NAD(P)H:quinone oxidoreductase 1 (NQO1) protein protects cells against redox cycling of quinones and oxidative stress. Oxidative stress represents key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NQO1 in AAA formation has not been investigated previously.Methods The Tandem Mass Tag (TMT) labeling quantitative proteomics technique was utilized to detect 3 AAA tissues and 3 corresponding adjacent normal abdominal aorta tissue specimens. Immunohistochemistry was used to detect NQO1 expression in 8 AAA tissues, and the correlation with AAA size, MDA and SOD levels was analyzed. The senescence model of human vascular smooth muscle cell (VSMCs) induced by Angiotensin II (AngII) was established in vitro. The effect of AngII on the level of reactive oxygen species (ROS) and β-galactosidase activity of VSMCs were observed after NQO1 expression was inhibited by specific interfering RNA (si-NQO1) technique.Results NQO1 expression was the highest up-regulation (3.1fold) among 11 differentially expressed oxidative stress-related proteins (> 1.2 or<0.83 and P<0.05), and the expression of NQO1 was positively correlated with the AAA size (R2=0.517, P<0.05) and MDA level (R2=0.659, P<0.05). AngII treatment of human VSMCs increased ROS expression and β-galactosidase activity, while knocking down NQO1 expression promoted AngII-induced ROS production and cell aging. Conclusion Up-regulation of NQO1expression plays an antioxidant role in AAA, and it is expected to be a biomarker for early diagnosis and prognosis assessment of AAA.

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“…Several investigations had previously suggested that HPV may be facilitated in part by calcium release from SR stores [ 52 , 61 , 62 , 63 , 64 ], but none had so clearly demonstrated that this was initiated independent voltage-gated calcium influx and endothelium-derived vasoconstrictors. Hence general acceptance of the dominant hypothesis of the time, that HPV was triggered by K V channel inhibition and consequent voltage-gated calcium influx [ 27 , 28 , 29 , 36 , 47 , 57 , 58 ], which had now been debunked, from my perspective at least.…”

Section: K N or Not K N Thatmentioning

confidence: 90%

“…The prevailing hypothesis back then was, and still now remains so in the eyes of some, that HPV is triggered by the inhibition of voltage-gated potassium channels, consequent membrane depolarisation and voltage-gated calcium influx [ 27 , 28 , 29 , 36 , 47 , 57 , 58 ].…”

Section: K N or Not K N Thatmentioning

confidence: 99%

On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web

Evans

2020

Molecules

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A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8‑bromo‑cADPR, had been developed and was made available to us. We used 8‑bromo‑cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8‑bromo‑cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8‑bromo‑cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8‑bromo‑cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes.

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Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction

Cited by 72 publications

References 60 publications

Possible silent hypoxemia in a COVID-19 patient: a case report

Possible silent hypoxemia in a COVID-19 patient: a case report

Expression of NAD(P)H:Quinone Oxidoreductase 1 and Its Significance in Human Abdominal Aortic Aneurysmal Tissues

On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web

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