Hypoxia increases Hsp90 binding to eNOS via PI3K-Akt in porcine coronary artery endothelium

Chen, Jianxiong; Meyrick, Barbara

doi:10.1038/labinvest.3700027

Cited by 84 publications

(53 citation statements)

References 47 publications

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“…Chen and Meyrick28 found that acute hypoxia stimulated Hsp90 binding to eNOS and activation of the PI3–Akt pathway resulting in increased eNOS phosphorylation. They suggested that this may be a mechanism whereby eNOS activity and subsequent NO production is upregulated in hypoxic coronary arteries.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Inhibits ACTH-Induced Cortisol Production in Near-Term, Long-Term Hypoxic Ovine Fetal Adrenocortical Cells

et al. 2010

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We previously reported that in the sheep fetus, long term hypoxia (LTH) resulted in elevated basal plasma ACTH1–39 while cortisol levels were not different from normoxic controls. We also showed that LTH enhances endothelial nitric oxide synthase (eNOS) expression in the fetal adrenal. This study was designed to determine the effect of nitric oxide on cortisol production in adrenocortical cells from LTH fetal sheep. Ewes were maintained at high altitude (3,820 m) from ~40 days’ gestation (dG) to near term. Between 138–141 dG, fetal adrenal glands were collected from LTH and age-matched normoxic control fetuses. Adrenal cortical cells were pre-treated with sodium nitroprusside (SNP), L-NAME, L-arginine, or Diethyleneamine nitric oxide (DETA-NO) then challenged with 10nM ACTH. Cortisol responses were compared after 1 h. ACTH induced cortisol secretion was significantly higher in LTH vs. control (p<0.01). Enhancement of nitric oxide with L-arginine resulted in a significant reduction of ACTH-mediated cortisol production in the LTH group. DETA-NO also caused a significant decrease in ACTH-mediated cortisol production (p<0.05). Inhibition of NOS with L-NAME significantly increased cortisol production in the LTH group (p<0.05 compared to ACTH alone) while the effect on the control group was not significant. NOS activity was significantly higher in the LTH group compared to control but this difference was eliminated following ACTH treatment. These data indicate that LTH enhances adrenal cortical sensitivity to the inhibitory effects of NO on cortisol production. NO may therefore play an important role in regulating ACTH-induced cortisol production in the LTH fetal adrenal.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Inhibits ACTH-Induced Cortisol Production in Near-Term, Long-Term Hypoxic Ovine Fetal Adrenocortical Cells

et al. 2010

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“…For hypoxia studies [24], the cells were exposed to normoxia (PO 2 = 160 mmHg) or hypoxia (PO 2 < 10 mmHg) for various time periods with basic medium containing 0.1% FBS in normal incubator or an air-tight chamber (MIC-101, Billups-Rothenberg, Inc.) flushed with 95% N 2 /5% CO 2 . The cells were then immediately harvested for western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction

Zeng

Chen

et al. 2017

Journal of Molecular and Cellular Cardiology

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Endothelial glycolysis plays a critical role in the regulation of angiogenesis. We investigated the role of Sirtuin 3 (SIRT3) on endothelial cell (EC) glycolytic metabolism, angiogenesis, and diastolic function. Our aim was to test the hypothesis that loss of SIRT3 in ECs impairs endothelial glycolytic metabolism and angiogenesis and contributes to myocardial capillary rarefaction and the development of diastolic dysfunction. Using SIRT3 deficient ECs, SIRT3 was found to regulate a metabolic switch between mitochondrial respiration and glycolysis. SIRT3 knockout (KO)-ECs exhibited higher mitochondrial respiration and reactive oxygen species (ROS) formation. SIRT3 knockout (KO)-ECs exhibited a reduction in the expression of glycolytic enzyme, PFKFB3, and a fall in glycolysis and angiogenesis. Blockade of PFKFB3 reduced glycolysis and downregulated expression of VEGF and Angiopoietin-1 (Ang-1) in ECs. Deletion of SIRT3 in ECs also impaired hypoxia-induced expression of HIF-2α, VEGF, and Ang-1, as well as reduced angiogenesis. In vivo, endothelial-specific SIRT3 KO (ECKO) mice exhibited a myocardial capillary rarefaction together with a reduced coronary flow reserve (CFR) and diastolic dysfunction. Histologic study further demonstrated that knockout of SIRT3 in ECs significantly increased perivascular fibrosis in the coronary artery. These results implicate a role of SIRT3 in modulating endothelial function and cardiac function. Ablation of SIRT3 leads to impairment of EC glycolytic metabolism and angiogenic signaling, which may contribute to coronary microvascular rarefaction and diastolic dysfunction in SIRT3 ECKO mice.

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“…HIF-1 increases the expression of endothelial nitric oxide synthase (eNOS) and the extent of eNOS phosphorylation (Chen and Meyrick, 2004; Dedkova et al , 2004; Shi et al , 2002), HIF-1 suppresses SDHB (Dahia et al , 2005), stimulates expression of PDK and LDHA (Firth et al , 1995; Kim et al , 2006; Papandreou et al , 2006; Semenza et al , 1996) and is involved in the regulation of mitochondrial mass via inhibition of biogenesis (Zhang et al , 2007) and the stimulation of mitochondrial autophagy (Zhang et al , 2008). …”

Section: Hypoxia and Hif-1 Mediation Of Metabolic Reprogrammingmentioning

confidence: 99%

Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth?

Illsley¹,

Caniggia²,

Zamudio³

2010

Int. J. Dev. Biol.

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Insufficient oxygen leads to the cessation of growth in favor of cellular survival. Our unique model of high-altitude human pregnancy indicates that hypoxia-induced reductions in fetal growth occur at higher levels of oxygen than previously described. Fetal PO2 is surprisingly high and fetal oxygen consumption unaffected by high altitude, whereas fetal glucose delivery and consumption decrease. Placental delivery of energy-generating substrates to the fetus is thus altered by mild hypoxia, resulting in maintained fetal oxygenation but a relative fetal hypoglycemia. Our data point to this altered mix of substrates as a potential initiating factor in reduced fetal growth, since oxygen delivery is adequate. These data support the existence, in the placenta, of metabolic reprogramming mechanisms, previously documented in tumor cells, whereby HIF-1 stimulates reductions in mitochondrial oxygen consumption at the cost of increased glucose consumption. Decreased oxygen consumption is not due to substrate (oxygen) limitation but rather results from active inhibition of mitochondrial oxygen utilization. We suggest that under hypoxic conditions, metabolic reprogramming in the placenta decreases mitochondrial oxygen consumption and increases anerobic glucose consumption, altering the mix of energy-generating substrates available for transfer to the fetus. Increased oxygen is available to support the fetus, but at the cost of less glucose availability, leading to a hypoglycemia-mediated decrease in fetal growth. Our data suggest that metabolic reprogramming may be an initiating step in the progression to more severe forms of fetal growth restriction and points to the placenta as the pivotal source of fetal programming in response to an adverse intrauterine environment.

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Hypoxia increases Hsp90 binding to eNOS via PI3K-Akt in porcine coronary artery endothelium

Cited by 84 publications

References 47 publications

Nitric Oxide Inhibits ACTH-Induced Cortisol Production in Near-Term, Long-Term Hypoxic Ovine Fetal Adrenocortical Cells

Nitric Oxide Inhibits ACTH-Induced Cortisol Production in Near-Term, Long-Term Hypoxic Ovine Fetal Adrenocortical Cells

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction

Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth?

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