HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes

Shimoda, Larissa A.; Fallon, Michele; Pisarcik, Sarah; Wang, Jian; Semenza, Gregg L.

doi:10.1152/ajplung.00528.2005

Cited by 184 publications

(195 citation statements)

References 49 publications

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“…Despite a low pHe, the intracellular pH (pHi) of tumour cells is maintained at a relatively normal pH or even slightly more alkaline pH, which is reported to result from HIF-mediated up-regulation and activation of a number of membrane located transporters, exchanges, pumps and ecto-enzymes that are implicated in pH homeostasis. Among these are the growth factor activatable and amiloride-sensitive Na + /H + Exchanger (NHE-1) [32][33][34] and the H + /lactate cotransporter (monocarboxylate transporter, MCT1 and MCT4) [35]. In addition, one of the most highly HIF-induced proteins, carbonic anhydrase IX (CA IX), an enzyme that catalyzes the reversible conversion of CO 2 to carbonic acid (Fig.…”

Section: Regulation Of Phmentioning

confidence: 99%

Hypoxia and cancer

2007

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A major feature of solid tumours is hypoxia, decreased availability of oxygen, which increases patient treatment resistance and favours tumour progression. How hypoxic conditions are generated in tumour tissues and how cells respond to hypoxia are essential questions in understanding tumour progression and metastasis. Massive tumour-cell proliferation distances cells from the vasculature, leading to a deficiency in the local environment of blood carrying oxygen and nutrients. Such hypoxic conditions induce a molecular response, in both normal and neoplastic cells, that drives the activation of a key transcription factor; the hypoxia-inducible factor. This transcription factor regulates a large panel of genes that are exploited by tumour cells for survival, resistance to treatment and escape from a nutrient-deprived environment. Although now recognized as a major contributor to cancer progression and to treatment failure, the precise role of hypoxia signalling in cancer and in prognosis still needs to be further defined. It is hoped that a better understanding of the mechanisms implicated will lead to alternative and more efficient therapeutic approaches.

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Section: Regulation Of Phmentioning

confidence: 99%

Hypoxia and cancer

2007

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“…HIF-1α regulates PASMC K v + capacitance, K + current density, and membrane depolarization, which are decreased in HIF-1α-+/− cells [48]. After exposure to chronic hypoxia, wild-type PASMCs increase the expression and activity of Na + /H + exchanger (NHE), which results in increased intracellular pH and cell growth [49]. Recent reports indicate that hypoxic PASMCs have increased expression of canonical transient receptor potential (TRPC) channels 1 and 6 in a HIF-1α-dependent manner [50].…”

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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“…In particular, decreased HIF-2α levels result in lower pulmonary pressure, the absence of RV hypertrophy, and reduced expression of ET-1 (39). Furthermore, HIF-1α regulates pulmonary artery myocyte electrophysiology (40)(41)(42) and promotes the proliferation of vascular smooth muscle cells (43), whereas HIF-2α enhances the proliferation and migration of pulmonary artery fibroblasts (44).…”

Section: Introductionmentioning

confidence: 99%

The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice

Hickey¹,

Richardson²,

Wang³

et al. 2010

J. Clin. Invest.

129

139

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Mutation of the von Hippel-Lindau (VHL) tumor suppressor protein at codon 200 (R200W) is associated with a disease known as Chuvash polycythemia. In addition to polycythemia, Chuvash patients have pulmonary hypertension and increased respiratory rates, although the pathophysiological basis of these symptoms is unclear. Here we sought to address this issue by studying mice homozygous for the R200W Vhl mutation (Vhl R/R mice) as a model for Chuvash disease. These mice developed pulmonary hypertension independently of polycythemia and enhanced normoxic respiration similar to Chuvash patients, further validating Vhl R/R mice as a model for Chuvash disease. Lungs from Vhl R/R mice exhibited pulmonary vascular remodeling, hemorrhage, edema, and macrophage infiltration, and lungs from older mice also exhibited fibrosis. HIF-2α activity was increased in lungs from Vhl R/R mice, and heterozygosity for Hif2a, but not Hif1a, genetically suppressed both the polycythemia and pulmonary hypertension in the Vhl R/R mice. Furthermore, Hif2a heterozygosity resulted in partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, in Vhl R/R lungs, suggesting a selective role for HIF-2α in the pulmonary pathology and thereby providing insight into the mechanisms underlying pulmonary hypertension. These findings strongly support a dependency of the Chuvash phenotype on HIF-2α and suggest potential treatments for Chuvash patients.

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HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes

Cited by 184 publications

References 49 publications

Hypoxia and cancer

Hypoxia and cancer

Hypoxia and chronic lung disease

The von Hippel–Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice

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