Ghrelin and Its Relation with N-Terminal Brain Natriuretic Peptide, Endothelin-1 and Nitric Oxide in Patients with Idiopathic Pulmonary Hypertension

Yang, Dan; Liu, Zhihong; Yang, Zihe

doi:10.1159/000348368

Cited by 20 publications

(19 citation statements)

References 27 publications

(37 reference statements)

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“…In present study, pre-treatment with ghrelin did not have a notable influence on the iNOS protein expression in A549 cells induced by LPS, although it alone appeared to decrease the iNOS protein expression. Interestingly, our data showed that ghrelin could inhibit the NO production in A549 cells induced by LPS treatment, which was in contrast to what Yang et al reported that the NO production is in accordance with the increased plasma ghrelin levels in patients with idiopathic pulmonary arterial hypertension (IPAH) [35]. This contradiction may be attributable to that a small amount of NO could enhance vasodilation and regulate blood pressure [36,37], but excessive NO production, therefore, exert a harmful role.…”

Section: Discussioncontrasting

confidence: 99%

Effects of Ghrelin on iNOS-Derived NO Promoted LPS-Induced Pulmonary Alveolar Epithelial A549 Cells Apoptosis

Zeng

Huang

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: In the process of abnormal apoptosis of pulmonary alveolar type II epithelial A549 cells in acute respiratory distress syndrome (ARDS), inducible nitric oxide synthase (iNOS) activity in the lung, nitric oxide (NO) production, and the level of protein S-nitrosylation were increased. However, the role of excessive NO production in sepsis-induced ARDS is controversial. Additionally, ghrelin is a growth hormone that exerts an inhibitory role in cell apoptosis. We examined the effect of NO and S-nitrosylation on apoptosis of A549 cells induced by Lipopolysaccharide (LPS) and molecular mechanism underlying the anti-apoptotic effect of ghrelin in this process. Methods: Flow cytometry and qPCR were used to detect lentiviral infection efficiency and iNOS gene level, respectively. Extracellular and intracellular NO levels were observed by Griess assay kit and DAF-FM DA. Mitochondrial transmembrane potential, apoptosis rate and SNO levels were determined by flow cytometry, Biotin-Switch method and immunofluoresence staining. The expression of iNOS, apoptotic proteins and JNK were assessed by immunoblot analysis. Results: The results showed about two times increase in iNOS expression and intracellular NO levels response to LPS exposure at 24 hours (P< 0.05), while not in extracellular NO levels. NO donors, S-nitroso-N-acetylpenicillamine (SNAP) significantly raised (36.7%, P< 0.05; 38.4%, P< 0.05; 41.8%, P< 0.05) extracellular NO levels without influencing the intracellular NO levels. LPS increased the apoptosis rate (42.4%±2.6% vs 2.8%±1%, P< 0.05) of A549 accompanied by increased Bax levels and decreased Bcl-2 levels through activating JNK signaling, which was reversed when we diminished the iNOS expression in A549 cells using lentiviral vectors encoding iNOS shRNA in the presence of LPS (24.8%±3.8% vs 42.4%±2.6%, P< 0.05). However, the apoptosis rate was increased when SNAP was added (38.8%±1.3% vs 24.8%±3.8%, P< 0.05). Furthermore, we investigated whether ghrelin exert a protective role against LPS-induced apoptosis and the potential mechanism involved in. Ghrelin alone appeared to decrease iNOS expression (32.3%, P< 0.05; 42.3%, P< 0.05), which showed no signifiant difference between LPS+ghrelin group and LPS group. However, this study showed that ghrelin decreased the intracellular NO production (38.9%, P< 0.05), protein S-nitrosylation levels (33.5%, P< 0.05), Bax protein expression (70.2%, P< 0.05), whereas increasing Bcl-2 protein expression (14.1%, P< 0.05) and mitochondrial transmembrane potential (∆ΨM) (20.7%, P< 0.05) in the presence of LPS. Conclusion: The data suggested that NO derived from iNOS induced by LPS stimulation exerts an important role in promoting apoptosis of A549 cells, and ghrelin abolished intracellular NO production and protein S-nitrosylation levels, abrogating the apoptosis of A549 cells partly through inhibiting mitochondrial-dependent pathways.

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Section: Discussioncontrasting

confidence: 99%

Effects of Ghrelin on iNOS-Derived NO Promoted LPS-Induced Pulmonary Alveolar Epithelial A549 Cells Apoptosis

Zeng

Huang

Zheng

et al. 2018

Cell Physiol Biochem

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“…Plasma BNP levels are elevated in adults and children with heart disease and PAH (idiopathic or congenital), so these levels serve as a useful laboratory parameter in medical or surgical treatment [23,24]. In our study we showed that all of the PAH patients had elevated levels of plasma BNP.…”

Section: Discussionsupporting

confidence: 51%

The Effects of Perioperative Inhaled Iloprost on Pulmonary Hypertension with Congenital Heart Disease

et al. 2013

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Objectives: The treatment of choice for congenital heart disease (CHD) with pulmonary arterial hypertension (PAH) is still controversial. We assessed the efficacy and safety of perioperative inhaled iloprost therapy in CHD with PAH. Methods: Among 45 patients with a ventricular septal defect and/or an atrial septal defect with PAH, 28 patients were treated with inhaled iloprost before and after surgery. Perioperative clinical parameters and plasma B-type natriuretic peptide (BNP) were evaluated. Results: No statistical difference in the estimated right ventricular systolic pressure (e-RVP), the e-RVP-to-systemic pressure ratio, and preoperative BNP levels between the iloprost group and the control group were found. Among the iloprost group, oxygen saturation was increased significantly after iloprost inhalation therapy (p = 0.0052). The iloprost group was also significantly correlated with less use of inhaled nitric oxide in the immediate postoperative period compared to the control group (p = 0.021). The durations of mechanical ventilation (p = 0.018), ICU stay (p = 0.005), and chest tube use (p = 0.039) were significantly shorter in the iloprost group compared to the control group. The plasma BNP, checked on 7th day of postoperatively, was lower in the iloprost group than in the control group (p = 0.008). Conclusion: Perioperative inhaled iloprost therapy showed the benefit of cardiac functional improvement and early weaning of postoperative supportive care in the management of CHD with PAH.

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“…Ghrelin levels are three-fold higher in women than in men (90). Increased levels of circulating ghrelin are observed in IPAH (91). However, paradoxically, in MCT or hypoxic rat models the administration of ghrelin reduces PH (92,93).…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 98%

“…Thus, ghrelin is protective in rodent models but elevated in IPAH. In this instance, ghrelin has a central effect (stimulates GHRH and thus GH secretion, as in humans) and a different peripheral effect (antagonizes endothelin-1) (91).…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Ghrelin and Its Relation with N-Terminal Brain Natriuretic Peptide, Endothelin-1 and Nitric Oxide in Patients with Idiopathic Pulmonary Hypertension

Cited by 20 publications

References 27 publications

Effects of Ghrelin on iNOS-Derived NO Promoted LPS-Induced Pulmonary Alveolar Epithelial A549 Cells Apoptosis

Effects of Ghrelin on iNOS-Derived NO Promoted LPS-Induced Pulmonary Alveolar Epithelial A549 Cells Apoptosis

The Effects of Perioperative Inhaled Iloprost on Pulmonary Hypertension with Congenital Heart Disease

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

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