Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension

Niihori, Maki; Eccles, Cody A.; Kurdyukov, Sergey; Zemskova, Marina; Varghese, Mathews Valuparampil; Степанова, Анна; Galkin, Alexander; Rafikov, Ruslan; Rafikova, Olga

doi:10.1165/rcmb.2019-0065oc

Cited by 31 publications

(44 citation statements)

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“…We also recently showed that rats with a mutation in NFU1 protein develop pulmonary arterial hypertension with a remarkable demonstration of sexual dimorphism as found in humans. Interestingly, in the NFU1 rat model, we found that the prevalence of the disease is more pronounced in female rats than in males [31]. In the present study, we found that the early MCT model indicates that males are more prone to develop hemolysis, and they showed increased pulmonary pressure and remodeling.…”

Section: Discussionsupporting

confidence: 50%

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

et al. 2020

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Background: The mechanisms involved in pulmonary hypertension (PH) development in patients and pre-clinical models are poorly understood. PH has a well-established sex dimorphism in patients with increased frequency of PH in females, and more severe disease with poor survival prognosis in males. Previously, we found that heme signaling plays an essential role in the development phase of the Sugen/Hypoxia (SU/Hx) model. This study is focused on the elucidation of sex differences in mechanisms of PH development related to heme action at the early stage of the monocrotaline (MCT) PH model. Methods: Rats received MCT injection (60 mg/kg, i.p.) and followed for 14 days to investigate early disease changes. Hemodynamic parameters were recorded at the end of the study; plasma, lung homogenates, and nuclear fractions were used for the evaluation of protein levels. Results: Our data indicate that on day 14, rats did not show any significant increase in the Fulton index due to the early disease phase. However, the right ventricular systolic pressure was significantly increased in male rats, while female rats showed only a trend. Interestingly, only males demonstrated an increased lung-to-bodyweight ratio that indicated lung edema. Indeed, lung histology confirmed severe perivascular edema in males. Previously, we have reported that the increased perivascular edema in SU/Hx model correlated with intravascular hemolysis and activated heme signaling. Here, we found that elevated free hemoglobin levels and perivascular edema were increased, specifically in males showing more rapid progress of PH. A high level of heme carrier protein 1 (HCP-1), which is involved in heme uptake from the bloodstream into the cells, was also found elevated in the lungs of males. The upregulation of heme oxygenase in males indicated increased intracellular heme catabolism. Increased heme signaling resulted in the activation of heme-mediated barrier-disruptive mechanisms. Thus, hemolysis in males can be responsible for increased permeability of the lungs and early disease development. Conclusions: Our study indicates the importance of barrier-disruptive mechanisms as an earlier event in the induction of pulmonary hypertension. Importantly, males are more susceptible to hemolysis and develop PH earlier than females.

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confidence: 50%

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

et al. 2020

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“…For instance, reduced mitochondrial superoxide dismutase 2 (SOD2) levels were found in PASMCs of PAH patients and blunted SOD2 function ensues an apoptosis-resistant phenotype of PASMCs, which may foster PASMC accumulation in pulmonary vessels of PH patients [71]. In line with this, the mitochondrial ironsulfur cluster scaffold Protein NFU1 is linked to heritable forms of PAH, and the autosomal recessive inheritance of the NFU1 mutation G208C causes PAH in approximately 70% of affected cases [72].…”

Section: Interconnection Of Pulmonary Hypertension Iron Homeostasis mentioning

confidence: 95%

Anaemia, iron homeostasis and pulmonary hypertension: a review

et al. 2020

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Anaemia is a highly prevalent condition, which negatively impacts on patients' cardiovascular performance and quality of life. Anaemia is mainly caused by disturbances of iron homeostasis. While absolute iron deficiency mostly as a consequence of chronic blood loss or insufficient dietary iron absorption results in the emergence of iron deficiency anaemia, inflammation-driven iron retention in innate immune cells and blockade of iron absorption leads to the development of anaemia of chronic disease. Both, iron deficiency and anaemia have been linked to the clinical course of pulmonary hypertension. Various mechanistic links between iron homeostasis, anaemia, and pulmonary hypertension have been described and current treatment guidelines suggest regular iron status assessment and the implementation of iron supplementation strategies in these patients. The pathophysiology, diagnostic assessment as well as current and future treatment options concerning iron deficiency with or without anaemia in individuals suffering from pulmonary hypertension are discussed within this review.

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“… 10 Also, abnormalities in Fe-S cluster transfer to client proteins have been shown to be associated with cardiovascular diseases. 10 , 11 We recently established that the G206C mutation in NFU1 in rats demonstrates a similar PAH pathology as found in humans with the NFU1 G208C mutation, 12 making it the first humanized genetic rat preclinical model of PAH. 13 It was also recently highlighted that there needs to be further investigation into PAH in the context of Fe-S biology.…”

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Single Mutation in the NFU1 Gene Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells

James

Zemskova

Eccles

et al. 2021

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Objective: NFU1 is a mitochondrial iron-sulfur scaffold protein, involved in iron-sulfur assembly and transfer to complex II and LAS (lipoic acid synthase). Patients with the point mutation NFU1 G208C and CRISPR/CAS9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9)-generated rats develop mitochondrial dysfunction leading to pulmonary arterial hypertension. However, the mechanistic understanding of pulmonary vascular proliferation due to a single mutation in NFU1 remains unresolved. Approach and Results: Quantitative proteomics of isolated mitochondria showed the entire phenotypic transformation of NFU1 G206C rats with a disturbed mitochondrial proteomic landscape, involving significant changes in the expression of 208 mitochondrial proteins. The NFU1 mutation deranged the expression pattern of electron transport proteins, resulting in a significant decrease in mitochondrial respiration. Reduced reliance on mitochondrial respiration amplified glycolysis in pulmonary artery smooth muscle cell (PASMC) and activated GPD (glycerol-3-phosphate dehydrogenase), linking glycolysis to oxidative phosphorylation and lipid metabolism. Decreased PDH (pyruvate dehydrogenase) activity due to the lipoic acid shortage is compensated by increased fatty acid metabolism and oxidation. PASMC became dependent on extracellular fatty acid sources due to upregulated transporters such as CD36 (cluster of differentiation 36) and CPT (carnitine palmitoyltransferase)-1. Finally, the NFU1 mutation produced a dysregulated antioxidant system in the mitochondria, leading to increased reactive oxygen species levels. PASMC from NFU1 rats showed apoptosis resistance, increased anaplerosis, and attained a highly proliferative phenotype. Attenuation of mitochondrial reactive oxygen species by mitochondrial-targeted antioxidant significantly decreased PASMC proliferation. Conclusions: The alteration in iron-sulfur metabolism completely transforms the proteomic landscape of the mitochondria, leading toward metabolic plasticity and redistribution of energy sources to the acquisition of a proliferative phenotype by the PASMC.

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Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension

Cited by 31 publications

References 44 publications

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

Anaemia, iron homeostasis and pulmonary hypertension: a review

Single Mutation in the NFU1 Gene Metabolically Reprograms Pulmonary Artery Smooth Muscle Cells

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