New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension

Kurdyukov, Sergey; Eccles, Cody A.; Desai, Ankit A.; Gonzalez-Garay, Manuel L.; Yuan, Jason X.‐J.; Garcia, Joe G.N.; Rafikova, Olga; Rafikov, Ruslan

doi:10.1371/journal.pone.0203493

Cited by 22 publications

(19 citation statements)

References 21 publications

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“…This could downregulate PPP and redirect the metabolism towards increased glycolysis, similar to what we found in a recent complex III-deficient model [7]. In accordance with this, our recent report in PAH patients suggests that G6PD deficiency potentiates hemolysis and disease progression [45]. In the two-week sugen/hypoxic model, nitro Akt activation maintained G6PD expression and corrected the PPP, thus balancing glycolytic metabolism to normal.…”

Section: Discussionsupporting

confidence: 89%

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

et al. 2020

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Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder instigated by pulmonary vascular cell proliferation. Activation of Akt was previously reported to promote vascular remodeling. Also, the irreversible nitration of Y350 residue in Akt results in its activation. NitroAkt was increased in PAH patients and the SU5416/Hypoxia (SU/Hx) PAH model. This study investigated whether the prevention of Akt nitration in PAH by Akt targeted nitroxide-conjugated peptide (NP) could reverse vascular remodeling and metabolic reprogramming. Treatment of the SU/Hx model with NP significantly decreased nitration of Akt in lungs, attenuated right ventricle (RV) hypertrophy, and reduced RV systolic pressure. In the PAH model, Akt-nitration induces glycolysis by activation of the glucose transporter Glut4 and lactate dehydrogenase-A (LDHA). Decreased G6PD and increased GSK3β in SU/Hx additionally shunted intracellular glucose via glycolysis. The increased glycolytic rate upregulated anaplerosis due to activation of pyruvate carboxylase in a nitroAkt-dependent manner. NP treatment resolved glycolytic switch and activated collateral pentose phosphate and glycogenesis pathways. Prevention of Akt-nitration significantly controlled pyruvate in oxidative phosphorylation by decreasing lactate and increasing pyruvate dehydrogenases activities. Histopathological studies showed significantly reduced pulmonary vascular proliferation. Based on our current observation, preventing Akt-nitration by using an Akt-targeted nitroxide-conjugated peptide could be a useful treatment option for controlling vascular proliferation in PAH.

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Section: Discussionsupporting

confidence: 89%

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

et al. 2020

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“…However, it is important to improve the early detection of PAH because functional class (FC) 1 and 2 patients with PAH have better survival rates than patients diagnosed in more severe conditions (67, 188). It can be argued that there is tremendous benefit in patients with risk factors such as familial PAH, sickle cell disease, thalassemia, glucose-6-phosphate dehydrogenase deficiency(87), portal hypertension, congenital heart disease, HIV infection, acute pulmonary embolism, and connective tissue disease(79), to undergo preventive assessment by echocardiography even in the absence of symptoms of PAH.…”

Section: Early Diagnosis/biomarkers Of Pahmentioning

confidence: 99%

Focus on Early Events: Pathogenesis of Pulmonary Arterial Hypertension Development

Rafikova

Ghouleh

Rafikov

2019

Antioxidants & Redox Signaling

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Significance: Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature characterized by the proliferation of all vascular wall cell types, including endothelial, smooth muscle, and fibroblasts. The disease rapidly advances into a form with extensive pulmonary vascular remodeling, leading to a rapid increase in pulmonary vascular resistance, which results in right heart failure. Recent Advances: Most current research in the PAH field has been focused on the late stage of the disease, largely due to an urgent need for patient treatment options in clinics. Further, the pathobiology of PAH is multifaceted in the advanced disease, and there has been promising recent progress in identifying various pathological pathways related to the late clinical picture. Critical Issues: Early stage PAH still requires additional attention from the scientific community, and although the survival of patients with early diagnosis is comparatively higher, the disease develops in patients asymptomatically, making it difficult to identify and treat early. Future Directions: There are several reasons to focus on the early stage of PAH. First, the complexity of late stage disease, owing to multiple pathways being activated in a complex system with intra-and intercellular signaling, leads to an unclear picture of the key contributors to the pathobiology. Second, an understanding of early pathophysiological events can increase the ability to identify PAH patients earlier than what is currently possible. Third, the prompt diagnosis of PAH would allow for the therapy to start earlier, which has proved to be a more successful strategy, and it ensures better survival in PAH patients. Antioxid. Redox Signal. 31, 933-953.

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“…Clinical reports connect G6PD deficiency with PAH [ 58 ]. More, three patients with missense mutations in the G2PD gene were identified in a cohort of PAH patients [ 59 ]. Altogether, these reports indicate that G6PD dysfunction could predispose one to the development of PAH.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Ribeuz

Dumont

Ruellou

et al. 2020

IJMS

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The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs.

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New cases of Glucose-6-Phosphate Dehydrogenase deficiency in Pulmonary Arterial Hypertension

Cited by 22 publications

References 21 publications

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

Antioxidant-Conjugated Peptide Attenuated Metabolic Reprogramming in Pulmonary Hypertension

Focus on Early Events: Pathogenesis of Pulmonary Arterial Hypertension Development

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

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