The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism

Slingo, Mary; Cole, Mark A.; Carr, Carolyn A.; Curtis, M. Kate; Dodd, Michael S.; Kartman, Bernt; Heather, Lisa C.; Tyler, Damian J.; Clarke, Kieran; Robbins, Peter A.

doi:10.1152/ajpheart.00912.2015

Cited by 11 publications

(7 citation statements)

References 67 publications

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“…Intracellular iron deficiency is known to stabilize HIF proteins through limiting the activity of iron- and oxygen-dependent prolyl hydroxylases. While we could not detect up-regulation of other HIF-target genes in iron-deficient PASMCs, this result is entirely consistent with the previous finding that ET-1 was the only HIF-target gene (among 10 targets tested) that increased in the lungs of mice with Chuvash polycythemia which have a moderate normoxic HIF accumulation (35). ET-1 is also a vasoconstrictor in the systemic circulation, and we did explore systemic hemodynamics in fpnC326Y fl/fl SMMHC-CreER T2+ mice.…”

Section: Discussionsupporting

confidence: 91%

Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice

Lakhal‐Littleton

Crosby

Frise

et al. 2019

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

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Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. Conversely, iron supplementation has been shown to be beneficial in both settings. The mechanisms underlying the effects of iron availability are not known, due to lack of understanding of how cells of the pulmonary vasculature respond to changes in iron levels. The iron export protein ferroportin (FPN) and its antagonist peptide hepcidin control systemic iron levels by regulating release from the gut and spleen, the sites of absorption and recycling, respectively. We found FPN to be present in pulmonary arterial smooth muscle cells (PASMCs) and regulated by hepcidin cell autonomously. To interrogate the importance of this regulation, we generated mice with smooth muscle-specific knock in of the hepcidin-resistant isoform fpn C326Y. While retaining normal systemic iron levels, this model developed PAH and right heart failure as a consequence of intracellular iron deficiency and increased expression of the vasoconstrictor endothelin-1 (ET-1) within PASMCs. PAH was prevented and reversed by i.v. iron and by the ET receptor antagonist BQ-123. The regulation of ET-1 by iron was also demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II. Such mutations were further associated with dysregulation of the HAMP/FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function. It offers a mechanistic underpinning for the known effects of iron availability in humans.

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Section: Discussionsupporting

confidence: 91%

Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice

Lakhal‐Littleton

Crosby

Frise

et al. 2019

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

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“…10,11 In addition, the use of animal models based on gene mutations suggests a multiplicity of pathways affecting cardiomyocytes such as transcriptional control, 12 calcium homeostasis, 13 force generation and transmission, 14 as well as metabolism. 15 The use of fast and cost-effective technologies, genetic testing based on the entire exome or genome sequencing 16 revealed a high number of variants which have little effect on cardiac health conditions. A number of polymorphisms have been suggested as a risk factor for heart diseases, however, most of these variants represent susceptibilities that require additional mutations or injury to cause the phenotype of disease.…”

Section: Origins Of Heart Diseasesmentioning

confidence: 99%

“…Mutations in a variety of genes have been associated with heart diseases in human 10 11 In addition, the use of animal models based on gene mutations suggests a multiplicity of pathways affecting cardiomyocytes such as transcriptional control, 12 calcium homeostasis, 13 force generation and transmission, 14 as well as metabolism 15 . The use of fast and cost-effective technologies, genetic testing based on the entire exome or genome sequencing 16 revealed a high number of variants which have little effect on cardiac health conditions.…”

Section: Origins Of Heart Diseasesmentioning

confidence: 99%

At the heart of programming: the role of micro-RNAs

Siddeek

Mauduit

Yzydorczyk

et al. 2018

J Dev Orig Health Dis

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Epidemiological and experimental observations tend to prove that environment, lifestyle or nutritional challenges influence heart functions together with genetic factors. Furthermore, when occurring during sensitive windows of heart development, these environmental challenges can induce an 'altered programming' of heart development and shape the future heart disease risk. In the etiology of heart diseases driven by environmental challenges, epigenetics has been highlighted as an underlying mechanism, constituting a bridge between environment and heart health. In particular, micro-RNAs which are involved in each step of heart development and functions seem to play a crucial role in the unfavorable programming of heart diseases. This review describes the latest advances in micro-RNA research in heart diseases driven by early exposure to challenges and discusses the use of micro-RNAs as potential targets in the reversal of the pathophysiology.

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“…Furthermore, Chuvash patients have increased pulmonary and vascular sensitivity to hypoxia and altered skeletal muscle metabolism [77, 78]. Metabolic alterations were also observed in the heart from mice homozygous for the Chuvash mutation [79]. Increased systolic pulmonary artery pressures were also found in patients with mutations in HIF2A and PHD2 [75, 80].…”

Section: Clinical Experience With Hif-prolyl Hydroxylase Inhibitors Amentioning

confidence: 99%

Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies

Haase

2017

Experimental Cell Research

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The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in the control of erythropoiesis and iron metabolism. The discovery of prolyl hydroxylase domain (PHD) proteins as key regulators of HIF activity has led to the development of inhibitory compounds that are now in phase 3 clinical development for the treatment of renal anemia, a condition that is commonly found in patients with advanced chronic kidney disease. This review provides a concise overview of clinical effects associated with pharmacologic PHD inhibition and was written in memory of Professor Lorenz Poellinger.

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The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism

Cited by 11 publications

References 67 publications

Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice

Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice

At the heart of programming: the role of micro-RNAs

Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies

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