Increased Nitrosoglutathione Reductase Activity in Hypoxic Pulmonary Hypertension in Mice

Wu, Xiling; Du, Lizhong; Xu, Xuefeng; Tan, Linhua; Li, Ruyi

doi:10.1254/jphs.09279fp

Cited by 19 publications

(12 citation statements)

References 27 publications

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“…However, other studies have measured right ventricular pressures and time-averaged CO. Right ventricular pressures in this study were similar to several prior studies (ϳ25 mmHg) (17,37,38,50,51,65) but higher than others (ϳ18 mmHg) (32,61), which may be due to the significantly slower heart rates in those studies compared with the present study. CO measured from the right ventricle in this study was similar to CO measured previously in the right ventricular by thermodilution (10) and estimated by transesophageal echocardiography (51), as well as left ventricular output measured by a variety of techniques (3,4,15,18,53).…”

Section: Discussionsupporting

confidence: 88%

Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops

Tabima¹,

Hacker

Chesler

2010

American Journal of Physiology-Heart and Circulatory Physiology

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Tabima DM, Hacker TA, Chesler NC. Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops. Am J Physiol Heart Circ Physiol 299: H2069 -H2075, 2010. First published October 8, 2010 doi:10.1152/ajpheart.00805.2010.-Mice are a widely used animal model for investigating cardiovascular disease. Novel technologies have been used to quantify left ventricular function in this species, but techniques appropriate for determining right ventricular (RV) function are less well demonstrated. Detecting RV dysfunction is critical to assessing the progression of pulmonary vascular diseases such as pulmonary hypertension. We used an admittance catheter to measure pressure-volume loops in anesthetized, open-chested mice before and during vena cava occlusion. Mice exposed to chronic hypoxia for 10 days, which causes hypoxia-induced pulmonary hypertension (HPH), were compared with control (CTL) mice. HPH resulted in a 27.9% increase in RV mass (P Ͻ 0.005), a 67.5% increase in RV systolic pressure (P Ͻ 0.005), and a 61.2% decrease in cardiac output (P Ͻ 0.05). Preload recruitable stroke work (PRSW) and slope of the maximum derivative of pressure (dP/dtmax)-end-diastolic volume (EDV) relationship increased with HPH (P Ͻ 0.05). Although HPH increased effective arterial elastance (Ea) over fivefold (from 2.7 Ϯ 1.2 to 16.4 Ϯ 2.5 mmHg/l), only a mild increase in the ventricular end-systolic elastance (Ees) was observed. As a result, a dramatic decrease in the efficiency of ventricular-vascular coupling occurred (Ees/Ea decreased from 0.71 Ϯ 0.27 to 0.35 Ϯ 0.17; P Ͻ 0.005). Changes in cardiac reserve were evaluated by dobutamine infusion. In CTL mice, dobutamine significantly enhanced Ees and dP/dtmax-EDV but also increased Ea, causing a decrease in Ees/Ea. In HPH mice, slight but nonsignificant decreases in Ees, PRSW, dP/dtmax-EDV, and Ea were observed. Thus 10 days of HPH resulted in RV hypertrophy, ventricular-vascular decoupling, and a mild decrease in RV contractile reserve. This study demonstrates the feasibility of obtaining RV pressure-volume measurements in mice. These measurements provide insight into ventricular-vascular interactions healthy and diseased states. cardiopulmonary hemodynamics; catheterization; chronic hypoxia; inotropic agents MOUSE IS A WIDELY USED SPECIES for investigating a growing number of disease states. In particular, the availability of knockout and transgenic mice allows the molecular mechanisms of disease to be understood with ever more clarity. Cardiopulmonary status, including right ventricular function, pulmonary vascular function, and right ventricular-pulmonary vascular interactions, is an important facet of health and disease. Recently, different methods for assessing left ventricular function, systemic vascular function, and the efficiency of left ventricular-systemic vascular hemodynamic interactions in mice in situ have been described (13,16,17,39,41,47,53,54,64). However, the feasibility and utility of these techniques in ...

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Section: Discussionsupporting

confidence: 88%

Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops

Tabima¹,

Hacker

Chesler

2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Hypoxic pulmonary hypertension model was established according to our previous experiments [30,31]. Briefly, 4-week IUGR rats and the age-matched control rats were placed in a normobaric hypoxic chamber with a fraction of inspiratory oxygen concentration of 12% for two weeks.…”

Section: Methodsmentioning

confidence: 99%

Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR

et al. 2013

Respir Res

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BackgroundAccumulating evidence reveals that intrauterine growth retardation (IUGR) can cause varying degrees of pulmonary arterial hypertension (PAH) later in life. Moreover, epigenetics plays an important role in the fetal origin of adult disease. The goal of this study was to investigate the role of epigenetics in the development of PAH following IUGR.MethodsThe IUGR rats were established by maternal undernutrition during pregnancy. Pulmonary vascular endothelial cells (PVEC) were isolated from the rat lungs by magnetic-activated cell sorting (MACS). We investigated epigenetic regulation of the endothelin-1 (ET-1) gene in PVEC of 1-day and 6-week IUGR rats, and response of IUGR rats to hypoxia.ResultsThe maternal nutrient restriction increased the histone acetylation and hypoxia inducible factor-1α (HIF-1α) binding levels in the ET-1 gene promoter of PVEC in IUGR newborn rats, and continued up to 6 weeks after birth. These epigenetic changes could result in an IUGR rat being highly sensitive to hypoxia later in life, causing more significant PAH or pulmonary vascular remodeling.ConclusionsThese findings suggest that epigenetics is closely associated with the development of hypoxic PAH following IUGR, further providing a new insight for improved prevention and treatment of IUGR-related PAH.

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“…Chronic exposure to hypoxia increases GSNOR protein expression (13). Western blot analysis was performed to determine whether the changes in GSNOR activity in response to acute hypoxia are due to changes in GSNOR protein expression.…”

Section: Changes In Gsnor Activity Are Associated With Changes In Gsnmentioning

confidence: 99%

“…Chronic hypoxia increases protein expression and activity of GSNOR in lung (13). However, little is known about the mechanisms that regulate GSNOR activity in the brainstem in response to an acute hypoxic exposure.…”

mentioning

confidence: 99%

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

Palmer

deRonde

Brown-Steinke

et al. 2015

Am J Respir Cell Mol Biol

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Exposure to hypoxia elicits an increase in minute ventilation that diminishes during continued exposure (roll-off). Brainstem Nmethyl-D-aspartate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS) contribute to the initial hypoxia-induced increases in minute ventilation. Roll-off is regulated by platelet-derived growth factor receptor-b (PDGFR-b) and S-nitrosoglutathione (GSNO) reductase (GSNOR). S-nitrosylation inhibits activities of NMDAR and nNOS, but enhances GSNOR activity. The importance of S-nitrosylation in the hypoxic ventilatory response is unknown. This study confirms that ventilatory roll-off is virtually absent in female GSNOR 1/2 and GSNO 2/2 mice, and evaluated the location of GSNOR in female mouse brainstem, and temporal changes in GSNOR activity, protein expression, and S-nitrosylation status of GSNOR, NMDAR (1, 2A, 2B), nNOS, and PDGFR-b during hypoxic challenge. GSNOR-positive neurons were present throughout the brainstem, including the nucleus tractus solitarius. Protein abundances for GSNOR, nNOS, all NMDAR subunits and PDGFR-b were not altered by hypoxia. GSNOR activity and S-nitrosylation status temporally increased with hypoxia. In addition, nNOS Snitrosylation increased with 3 and 15 minutes of hypoxia. Changes in NMDAR S-nitrosylation were detected in NMDAR 2B at 15 minutes of hypoxia. No hypoxia-induced changes in PDGFR-b Snitrosylation were detected. However, PDGFR-b phosphorylation increased in the brainstems of wild-type mice during hypoxic exposure (consistent with roll-off), whereas it did not rise in GSNOR 1/2 mice (consistent with lack of roll-off). These data suggest that: (1) S-nitrosylation events regulate hypoxic ventilatory response; (2) increases in S-nitrosylation of NMDAR 2B, nNOS, and GSNOR may contribute to ventilatory roll-off; and (3) GSNOR regulates PDGFR-b phosphorylation.Keywords: hypoxic ventilatory response; neuronal nitric oxide synthase; N-methyl-D-aspartate receptor; platelet-derived growth factor receptor-b; S-nitrosoglutathione reductase Clinical RelevanceThis article reports that the change in S-nitrosylation status of key brainstem proteins may underlie the roll-off phase of the hypoxic ventilatory response. This has potential clinical applications for understanding how mechanisms that affect S-nitrosothiol bioavailability (i.e., S-nitrosoglutathione reductase) play a role in central breathing disorders.

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Increased Nitrosoglutathione Reductase Activity in Hypoxic Pulmonary Hypertension in Mice

Cited by 19 publications

References 27 publications

Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops

Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops

Epigenetics of hypoxic pulmonary arterial hypertension following intrauterine growth retardation rat: epigenetics in PAH following IUGR

Hypoxia-Induced Changes in Protein S-Nitrosylation in Female Mouse Brainstem

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