Nitric oxide and pulmonary arterial pressures in pulmonary hypertension

Machado, Roberto F.; Nerkar, Medha Vini Londhe; Dweik, Raed A.; Hammel, Jeffrey; Janocha, Allison J.; Pyle, Jacqueline; Laskowski, Daniel; Jennings, Constance; Arroliga, Alejandro C.; Erzurum, Serpil C.

doi:10.1016/j.freeradbiomed.2004.06.039

Cited by 75 publications

(78 citation statements)

References 37 publications

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“…Serum uric acid levels decrease with successful treatment with prostacyclin of patients with IPAH [54]. Exhaled NO may be useful in the long-term monitoring of patients on prostacyclin [89] and bosentan [62].…”

Section: Response To Therapymentioning

confidence: 99%

Biomarkers in pulmonary hypertension

Warwick

Thomas²,

Yates³

2008

European Respiratory Journal

136

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There have been significant recent advances in the understanding of the pathophysiology of pulmonary hypertension, and a growing number of therapeutic agents have become available to the treating physician. Traditional methods of diagnosing and monitoring this condition have comprised echocardiography and right heart catheterisation, in addition to functional measures, such as estimation of functional class and the 6-min walk test. An increasing number of biomarkers have been described that are elevated in pulmonary hypertension and which may assist the clinician in diagnosis and in the assessment of disease severity and response to treatment.The present article details the more important biomarkers, their potential applications and the evidence supporting their use.

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Section: Response To Therapymentioning

confidence: 99%

Biomarkers in pulmonary hypertension

Warwick

Thomas²,

Yates³

2008

European Respiratory Journal

136

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“…5 Mice deficient in endothelial NO synthase (eNOS) are more sensitive to hypoxia-induced pulmonary hypertension, 6,7 whereas pulmonary gene transfer of eNOS is partially protective. 8 Patients with pulmonary hypertension have low NO levels in their exhaled breath, 9,10 and both inhaled NO and phosphodiesterase type 5 inhibitors, which act to increase NO-mediated cGMP signaling, have emerged as therapeutic strategies in pulmonary hypertension. Paradoxically, mice with hypoxia-induced pulmonary hypertension have increased eNOS protein levels without a concomitant increase in NO bioactivity.…”

Section: See P 2022mentioning

confidence: 99%

Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension

et al. 2005

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Background-Pulmonary hypertension is a fatal disease characterized by vasoconstriction and vascular remodeling. Loss of endothelial nitric oxide bioavailability is implicated in pulmonary hypertension pathogenesis. Recent evidence suggests that the cofactor tetrahydrobiopterin (BH4) is an important regulator of nitric oxide synthase enzymatic function. Methods and Results-In the hph-1 mouse with deficient BH4 biosynthesis, BH4 deficiency caused pulmonary hypertension, even in normoxic conditions, and greatly increased susceptibility to hypoxia-induced pulmonary hypertension. In contrast, augmented BH4 synthesis in the endothelium, by targeted transgenic overexpression of GTP-cyclohydrolase I (GCH), prevented hypoxia-induced pulmonary hypertension. Furthermore, specific augmentation of endothelial BH4 in hph-1 mice by crossing with GCH transgenic mice rescued pulmonary hypertension induced by systemic BH4 deficiency. Lung BH4 availability controlled pulmonary vascular tone, right ventricular hypertrophy, and vascular structural remodeling in a dose-dependent manner in both normoxia and hypoxia. Furthermore, BH4 availability had striking effects on the immediate vasoconstriction response to acute hypoxia. These effects of BH4 were mediated through the regulation of nitric oxide compared with superoxide synthesis by endothelial nitric oxide synthase. Conclusions-Endothelial BH4 availability is essential for maintaining pulmonary vascular homeostasis, is a critical mediator in the pathogenesis of pulmonary hypertension, and is a novel therapeutic target.

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“…The causal link between pulmonary hypertension and NO homeostasis has been extensively documented (26,36), and this is reflected clinically in the finding that intrapulmonary nitrates, biochemical reaction products of NO in bronchoalveolar fluid, and exhaled NO are all diminished in human pulmonary hypertension (37,38). Interestingly, primary pulmonary endothelial cells isolated from PAH patients have substantially increased expression of arg-2 (27), which would be predicted to decrease available L-arginine and reduce NOS-derived NO formation.…”

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.

152

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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Nitric oxide and pulmonary arterial pressures in pulmonary hypertension

Cited by 75 publications

References 37 publications

Biomarkers in pulmonary hypertension

Biomarkers in pulmonary hypertension

Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension

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

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