Partial HIF-1α deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia

Shimoda, Larissa A.; Manalo, Dominador J.; Sham, James S.K.; Semenza, Gregg L.; Sylvester, J. J.

doi:10.1152/ajplung.2001.281.1.l202

Cited by 195 publications

(162 citation statements)

References 30 publications

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“…In pulmonary artery smooth muscle cells (PASMC), hypoxia also inhibits K ϩ channel activity. When wild-type mice are exposed to 10% O 2 for 3 weeks, there is a marked reduction in membrane potential and K ϩ currents in PASMC, and this response is dramatically attenuated in Hif1a ϩ/Ϫ mice (29). A failure to down-regulate K ϩ channel activity may also contribute to the absence of hypoxic ventilatory adaptation in Hif1a ϩ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…Electrophysiological studies of glomus cells from wild-type and Hif1a ϩ/Ϫ mice will be required to test this hypothesis. In PASMC, partial HIF-1␣ deficiency impairs both the downregulation of K ϩ channel activity and development of cell hypertrophy, implicating HIF-1 in two major responses of PASMC to chronic hypoxia (29). HIF-1 may also play a multifactorial role in carotid body physiology.…”

Section: Discussionmentioning

confidence: 99%

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Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

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

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238

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To investigate whether the transcriptional activator hypoxiainducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O 2-regulated HIF-1␣ subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a ϩ/Ϫ mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a ϩ/Ϫ mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a ϩ/Ϫ mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a ϩ/Ϫ mice. Thus partial HIF-1␣ deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.O xygen homeostasis is mediated by the combined physiologic functioning of the circulatory and respiratory systems. Recent studies have demonstrated that the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for both the establishment of the circulatory system during embryonic development and physiologic responses in postnatal life. Analysis of Hif1a Ϫ/Ϫ knockout mice, which are homozygous for a lossof-function mutation in the Hif1a gene encoding the O 2 -regulated HIF-1␣ subunit, revealed that complete HIF-1␣ deficiency results in embryonic lethality at midgestation with major malformations of the heart and vasculature (1-3). Hif1a ϩ/Ϫ heterozygous mice, which are partially HIF-1␣ deficient, develop normally and are indistinguishable from their wild-type littermates under normoxic conditions. However, adult Hif1a ϩ/Ϫ mice manifest impaired physiological responses to chronic hypoxia including significantly reduced rates of erythropoiesis and pulmonary vascular remodeling (4). Thus HIF-1␣ plays essential roles in cardiac, erythroid, and vascular development and physiology, i.e., all three major components of the circulatory system.An essential adaptation to both acute and chronic hypoxia is an increase in ventilation that depends on the activity of peripheral chemoreceptors, particularly those within the carotid body, which detect changes in arterial blood O 2 concentration and relay sensory information to the brainstem neurons that regulate breathing (reviewed in ref. 5). Altered ventilatory responses to hypoxia may play a critical role in asthma, diabetes, Parkinson's disease, sleep-related breathing disorders, and sudden infant death syndrome (6-8). We hypothesized that HIF-1␣ is required for carotid body function and ventilatory adaptation to chronic hypoxia. To test this hyp...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

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

Self Cite

238

216

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“…HIF-2α, which is abundantly expressed in the lung, is also involved in PH, in that heterozygous mice are fully protected against PH and right ventricular hypertrophy caused by chronic hypoxia [47]. 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].…”

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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“…Mice that are hemizygous for either of the HIF isoforms, HIF-1α (14) or HIF-2α (15), have been shown to have attenuated pulmonary vascular remodeling following experimental CH. Conditional deletion of HIF-1α in smooth muscle also ameliorates the degree of remodeling in CH (16).…”

mentioning

confidence: 99%

“…The HIF pathway was implicated in PH initially through demonstrations showing that mice hemizygous for HIF-1α or HIF-2α have diminished levels of pulmonary hypertension (15,33); subsequent work was able to show that hemizygosity for HIF-1α resulted in changes in myocyte hypertrophy and polarization (14). In contrast, hemizygosity of HIF-2α revealed that endothelial changes resulting in PAH were partially blocked when HIF-2α was diminished (15).…”

mentioning

confidence: 99%

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Cowburn

Crosby

Macías

et al. 2016

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

157

158

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Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.A lveolar hypoxia affects vascular flow in the pulmonary vascular bed via an immediate vasoconstrictor response (hypoxic pulmonary vasoconstriction, or HPV) (1). This reduces perfusion of regions of the lung with lowered levels of airflow (2). In conditions including chronic obstructive pulmonary disease (3), idiopathic pulmonary fibrosis (4), and at high altitude (5), HPV probably contributes to persistent increases in pulmonary arterial pressures. This in turn is correlated with reduced plasticity of the vascular bed, sustained pulmonary vascular remodeling, and, ultimately, debilitating right ventricular hypertrophy (RVH) and failure (2).The hypoxia-inducible factors (HIFs) are transcription factors and key regulators of the molecular response to hypoxia. The targets of HIFs include genes controlling vascularization, cellular proliferation, migration, and metabolism (6-11). A wellcharacterized animal model of hypoxia-induced pulmonary hypertension involves exposure to chronic hypoxia (CH), typically 10-12% inspired oxygen. This results in extensive vascular remodeling, marked pulmonary hypertension and RVH over a period of a few weeks. Exposure to CH in rodents results in vasoconstriction and a pattern of vascular remodeling that is reminiscent of humans with hypoxia-associated pulmonary hypertension (12, 13).Mice that are hemizygous for either of the HIF isoforms, HIF-1α (14) or HIF-2α (15), have been shown to have attenuated pulmonary vascular remodeling following experimental CH. Conditional de...

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Partial HIF-1α deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia

Cited by 195 publications

References 30 publications

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Hypoxia and chronic lung disease

HIF2α–arginase axis is essential for the development of pulmonary hypertension

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