Decreased haptoglobin levels inversely correlated with pulmonary artery pressure in patients with pulmonary arterial hypertension

Nakamura, Hiroyuki; Kato, Masaaki; Nakaya, Toshitaka; Kono, Michihiro; Tanimura, Shun; Sato, Takahiro; Fujieda, Yuichiro; Oku, Kenji; Ohira, Hiroshi; Bohgaki, Toshiyuki; Yasuda, Shinsuke; Tsujino, Ichizo; Nishimura, Masaharu; Atsumi, Tatsuya

doi:10.1097/md.0000000000008349

Cited by 9 publications

(7 citation statements)

References 27 publications

(31 reference statements)

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“…Moreover, in another study, plasma free haemoglobin, was independently associated with increased risk for admission to hospital in PAH groups 28 . Furthermore, decreased levels of haptoglobin are seen in PAH phenotypes suggesting increased haemoglobin binding and removal in these patients 29 which is likely related to enhanced or on-going haemolysis. Studies presented herein suggest that free haemoglobin is also a pro-proliferative agent for hPASMCs and that the first description of the presence of CD163 on these cells suggests a means for cellular uptake of this iron containing protein complex.…”

Section: Discussionmentioning

confidence: 99%

The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells

Ramakrishnan

Pedersen

Toe

et al. 2018

Sci Rep

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Studies were undertaken to examine any role for the hepcidin/ferroportin axis in proliferative responses of human pulmonary artery smooth muscle cells (hPASMCs). Entirely novel findings have demonstrated the presence of ferroportin in hPASMCs. Hepcidin treatment caused increased proliferation of these cells most likely by binding ferroportin resulting in internalisation and cellular iron retention. Cellular iron content increased with hepcidin treatment. Stabilisation of ferroportin expression and activity via intervention with the therapeutic monoclonal antibody LY2928057 reversed proliferation and cellular iron accumulation. Additionally, IL-6 treatment was found to enhance proliferation and iron accumulation in hPASMCs; intervention with LY2928057 prevented this response. IL-6 was also found to increase hepcidin transcription and release from hPASMCs suggesting a potential autocrine response. Hepcidin or IL-6 mediated iron accumulation contributes to proliferation in hPASMCs; ferroportin mediated cellular iron excretion limits proliferation. Haemoglobin also caused proliferation of hPASMCs; in other novel findings, CD163, the haemoglobin/haptoglobin receptor, was found on these cells and offers a means for cellular uptake of iron via haemoglobin. Il-6 was also found to modulate CD163 on these cells. These data contribute to a better understanding of how disrupted iron homeostasis may induce vascular remodelling, such as in pulmonary arterial hypertension.

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Section: Discussionmentioning

confidence: 99%

The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells

Ramakrishnan

Pedersen

Toe

et al. 2018

Sci Rep

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“…It has been demonstrated that microvascular lesions cause diabetic ophthalmopathy and nephropathy and that DM-induced vascular injuries are a key factor in the development of microvascular lesions (8). Vascular endothelial cells serve important roles in maintaining the integrity of vascular structure and function (9,10). Patients with DM often exhibit damages to vascular endothelial cells (11).…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of microRNA‑199a‑3p is associated with vascular endothelial cell injury induced by type 2 diabetes mellitus

Wang

Tang

2018

Exp Ther Med

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The aim of the present study was to investigate the function and mechanism of action of microRNA (miRNA or miR)-199a-3p in vascular endothelial cell injury induced by type 2 diabetes mellitus (T2DM). A total of 36 patients with T2DM (26 males and 10 females; mean age, 52.5±7.0 years) and 20 healthy subjects (10 males and 10 females; mean age, 55.6±4.5 years) were included in the present study. Peripheral blood samples were obtained from all participants and total RNA was extracted Reverse transcription-quantitative polymerase chain reaction was performed to determine the expression of miR-199a-3p. Following the transfection of human umbilical vein endothelial cells (HUVECs) with a negative control (NC) miRNA or miR-199a-3p mimics, cell proliferation was assessed using a Cell Counting kit-8 assay. Cell migration was investigated using Transwell assays and flow cytometry was performed to detect the apoptosis of HUVECs. HUVECs were infected with Ad-GFP-LC3B and laser-scanning confocal microscopy was performed to observe autophagosomes in HUVECs. Western blotting was used to measure the expression of proteins associated with autophagy and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)-κB signaling pathway. MiR-199a-3p was downregulated in peripheral blood from patients with T2DM compared with healthy subjects. Transfection with miR-199a-3p mimics promoted the proliferation and migration of HUVECs. However, miR-199a-3p overexpression inhibited the apoptosis of HUVECs. MiR-199a-3p facilitated HUVEC autophagy by affecting autophagy-associated signaling pathways. Furthermore, miR-199a-3p regulated the biological functions of HUVECs via the PI3K/AKT/NF-κB signaling pathway. The results of the present study suggest that miR-199a-3p expression was reduced in patients with T2DM compared with healthy subjects and may be associated with vascular endothelial cell injury. In addition, miR-199a-3p promoted the proliferation, migration and autophagy of HUVECs, potentially by regulating the PI3K/AKT/NF-κB signaling pathway. Therefore, miR-199a-3p may function as protector of vascular endothelia.

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“…26,27 Except for the functions mentioned above, HAP also inhibits prostaglandin synthesis, antioxidant activity, promoting immune function, and angiogenesis. [27][28][29] Atsumi et al 30 have reported that serum HAP levels decreased in PH patients and inversely correlated with pulmonary artery pressure in PH related to connective tissue diseases (CTD) patients, suggesting their potential as a surrogate marker for PH-CTD. Buehler et al 31 have found that chronic HAP infusion was a novel therapy for chronic hemolysis-associated PH by preventing Hb-mediated vascular remodeling associated with hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Serum biomarker analysis at the protein level on pulmonary hypertension secondary to old anterior myocardial infarction

You

et al. 2020

Pulm. circ.

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Pulmonary hypertension (PH) related to old anterior myocardial infarction (OAMI) always accompanies a bad prognosis, and thus we aimed to screen serum biomarkers related to PH in OAMI patients. According to right ventricular systolic pressure (RVSP), we divided mice into sham, OAMI, and PH-OAMI groups and evaluated body, heart and lung weight, heart function, pulmonary blood flow velocity, cardiac fibrotic area, and pulmonary arteriole condition. Lung and serum were under the proteomic analysis. Levels of three identified proteins were measured. Compared with sham and OAMI mice, PH-OAMI mice showed heart dysfunction, low pulmonary blood flow, high RVSP, heavy heart and lung weight, large cardiac fibrotic area, and pathological pulmonary arteriole remodeling (P<0.05 or P<0.01). Haptoglobin, annexin A5 and Ig mu chain C region of lung and serum were changed significantly in PH-OAMI mice (P<0.01). Then, we collected serum and clinical data, measured three serum protein levels, and performed multivariate regression and receiver operating characteristic curve (ROC) in patients (normal, OAMI, and PH-OAMI groups). Compared with normal and OAMI patients, serum levels of three proteins in PH-OAMI patients were also altered notably (P<0.01). These three proteins can predict PH in OAMI patients (P<0.01). ROC analysis revealed haptoglobin (cut-off value: 78.295, sensitivity: 62.8%, Specificity: 94.4%), annexin A5 (cut-off value: 151.925, sensitivity: 41.9%, Specificity: 82.4%), and Ig mu chain C region (cut-off value: 168.885, sensitivity: 86.0%, Specificity: 79.6%) (P<0.01). Three circulating serum proteins can be useful for the categorization of OAMI patients with and without PH.

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Decreased haptoglobin levels inversely correlated with pulmonary artery pressure in patients with pulmonary arterial hypertension

Cited by 9 publications

References 27 publications

The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells

The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells

Reduced expression of microRNA‑199a‑3p is associated with vascular endothelial cell injury induced by type 2 diabetes mellitus

Serum biomarker analysis at the protein level on pulmonary hypertension secondary to old anterior myocardial infarction

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