Stimulation of HIF-1α, HIF-2α, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells

Asikainen, Tiina M.; Ahmad, Aftab; Schneider, Barbara; Ho, Wen‐Bin; Arend, Michael; Brenner, Mary E.; Günzler, Volkmar; White, Carl W.

doi:10.1016/j.freeradbiomed.2004.12.004

Cited by 85 publications

(100 citation statements)

References 82 publications

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“…Neither hypoxia nor inhibition leads to an increase of HIF-RNA but rather alters the P4H-mRNA [19]. We and others demonstrated that the P4-HI is capable of stabilizing and therefore inducing HIF protein [1,20] in vivo thus demonstrating the potential of a new non-peptide protein hydroxylase inhibitor as a pharmacological activator of the HIF pathway and as a therapeutic tool in treating ischemic diseases. Apparently the same system is involved in the progression of volume-overload induced left ventricular dilatation and reduction of cardiac function.…”

Section: Discussionmentioning

confidence: 79%

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Philipp¹

2012

J Clin Exp Cardiolog

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Introduction: Matrix reorganization and collagen formation have been suggested to be responsible for cardiac remodeling. Recently, Hypoxia Inducible Factors (HIF) has been shown to be also involved. To differentiate the pathogenesis of cardiac remodeling we used two different prolyl 4-hydroxylase (P4H) inhibitors, FG 0041 known for its potential in reducing collagen formation, FG 2216 for its capability to induce HIF. This study was performed to analyze whether the beneficial effects of P4-HI are mediated by induction of HIF or by effects on collagen metabolism.Methods: 8-week-old Wistar rats either had sham operations (n=14) or received Aortocaval Shunt (ACS). From day 2 rats received P4-HI (n=10 for each P4-HI) or vehicle (n=15) by oral gavage. Echocardiography was performed 28 days after ACS; hemodynamic measurements were done after 30 days. Activity of the metalloproteinase 2 and its inhibitor (TIMP), mRNA levels of CTGF, TGFß1, ITGß1 and Collagen I and III protein were measured.Results: After 30 days both HIF was induced in ACS. Treatment with FG 2216 led to an increase of HIF after 30 days compared to FG 0041 and vehicle. Only FG 2216 prevented left ventricular end-diastolic (7.9 mm vs. 9.8 mm; p<0.001) and end-systolic (4.1 vs. 6.0 mm, p<0.001) dilatation and improved left ventricular ejection fraction (85% vs. 74%, p<0.05). Heart weight (1416 ± 71 vs. 1871 ± 51 mg, p<0.001) and lung weight, as a marker for heart failure, (1958 ± 102 mg vs. 2276 ± 105 mg, p<0.05) were lower in the group receiving FG 2216. Collagen protein and metalloproteinase activity accompanying ACS were significantly decreased by FG 0041, but not by FG 2216. Conclusion:Induction of HIF improves cardiac function and reduces cardiac hypertrophy independent of changes in mRNA, collagen protein or metalloproteinase activity in this model of hypertrophy. Thus FG 2216 affects remodeling by directly targeting cardiomyocytes and has negligible effect on collagen production or extracellular matrix composition.

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Section: Discussionmentioning

confidence: 79%

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Philipp¹

2012

J Clin Exp Cardiolog

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“…Because hypoxic regulation of a large number of genes is mediated by HIF-1␣ and HIF-2␣, we evaluated the effect of HIF-stabilizing agents desferoxamine (DFO) and dimethyloxalylglycine (DMOG) at concentrations that we have demonstrated previously can stabilize both HIF-1␣ and HIF-2␣ (35). Fig.…”

Section: Resultsmentioning

confidence: 99%

Adenosine A _2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells

Ahmad

Glover

et al. 2009

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

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124

106

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“…Several of adolescent and adult BPD patients exhibit an emphysematous phenotype, potentially related to disruption of alveolar maintenance (see emphysema, below). The findings that PHDs control HIF degradation under normoxia and PHD activity is increased with increased oxygen availability [28] have offered new opportunities to develop therapies for BPD, as HIF-1α stabilization with PHD inhibitors improves lung growth and oxygenation [29].…”

Section: Hypoxia Signaling In the Lungmentioning

confidence: 99%

Hypoxia and chronic lung disease

et al. 2007

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The lung is both the conduit for oxygen uptake and is also affected by hypoxia and hypoxia signaling. Decreased ventilatory drive, airway obstructive processes, intra-alveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/arterial pO 2 gradient. These processes result in decreased blood and tissue oxygenation. This review addresses the relationship of hypoxia with lung development and with lung diseases. We particularly focus on molecular mechanisms underlying hypoxia-driven physiological and pathophysiological lung processes, specifically in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease.Keywords Hypoxia . Lung . Pathology . HIF Air, containing oxygen at approximately 21% partial pressure at sea level (140-150 mmHg), travels through up to 20 generations of airways by mass flow and then diffuses into the gas exchange units (alveoli) in the lung with a partial pressure of approximately 105-110 mmHg. The human lung contains approximately 480 million alveoli, which represent 64% of total lung structure. These alveoli are elegantly packed in only 1.3-2.6 L of total lung volume, providing a surface area of 120-150 m 2 , equivalent to the dimensions of a "tennis court" dedicated for gas exchange. Although the molecular determinants of lung size are not known, oxygen diffusion constant and gas exchange surface area are roughly proportional to body weight and oxygen consumption in different species [1]. Physical hyperactivity and exposure to a cold environment or high altitude lead to increased oxygen diffusion capacity, in proportion to enhanced oxygen consumption [1].Decreased ventilatory drive, airway obstructive processes, intraalveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/ arterial pO 2 gradient. This review addresses the contribution of hypoxia to lung diseases and the potential molecular mechanisms involved in hypoxia-driven physiological and pathophysiological lung processes (Fig. 1), particularly in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease. The fundamental concepts underlying hypoxia-induced gene expression and the molecular regulation of HIF(s) also apply to the lung, and they will be cited in relation to their demonstrated role in lung physiology or pathophysiology.

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Stimulation of HIF-1α, HIF-2α, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells

Cited by 85 publications

References 82 publications

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Adenosine A _2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells

Hypoxia and chronic lung disease

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Stimulation of HIF-1α, HIF-2α, and VEGF by prolyl 4-hydroxylase inhibition in human lung endothelial and epithelial cells

Cited by 85 publications

References 82 publications

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Induction of Hypoxia Inducible Factor Rather than Modulation of Collagen Metabolism Improves Cardiac Function and Reduces Left Ventricular Hypertrophy after Aortocaval Shunt in Rats

Adenosine A 2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells

Hypoxia and chronic lung disease

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Adenosine A _2A receptor is a unique angiogenic target of HIF-2α in pulmonary endothelial cells