Protective effects of the <i>Terminalia bellirica</i> tannin-induced Nrf2/HO-1 signaling pathway in rats with high-altitude pulmonary hypertension

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Abstract

Background

Oxidative stress and endothelial cell dysfunction induced by high-altitude hypoxia have important roles in the pathological process of high-altitude pulmonary hypertension (HAPH). Tannins present in Terminalia bellirica (Gaertn.) Roxb. (TTR) have pharmacological activities that produce oxidation resistance and exert anti-inflammatory effects. Whether TTR exerts a protective effect on HAPH remains unknown.

Methods

A rat model of HAPH was established. The mean pulmonary arterial pressure (mPAP) of the animals was measured, the serum levels of SOD, MDA, and GSH-Px were measured using ELISA, and the expression of Bax, Bcl-2, Nrf2, and HO-1 proteins in the lung tissue of each group of rats was measured using Western blotting. Pathological changes in the lung tissue were also observed. A model of damage to H ₂O ₂-induced pulmonary artery endothelial cells (PAECs) was generated, and cell proliferation was measured using CCK-8 assays. Flow cytometry was used to measure ROS levels in PAECs. Western blotting was used to detect the expression of Bax, Bcl-2, Nrf2, and HO-1 proteins in PAECs.

Results

The hemodynamic and pathologic findings showed that the mPAP of HAPH rats increased markedly, and the vascular wall thickness increased ( P < 0.05). TTR reduced mPAP, alleviated or slowed pulmonary arterial remodeling, increased GSH-Px and SOD activity, lowered the level of MDA ( P < 0.05), and downregulated the expression of Bax in the lung tissues of HAPH rats, while the expression of Bcl-2, Nrf2, and HO-1 was upregulated ( P < 0.05). The results of the cell experiments showed that TTR inhibited H ₂O ₂-induced PAEC apoptosis and ROS production ( P < 0.05), downregulated the expression of Bax in PAECs, and upregulated the expression of Bcl-2, Nrf2, and HO-1 ( P < 0.05).

Conclusion

The results suggest that TTR reduces pulmonary arterial pressure, decreases oxidative stress during HAPH, and exerts protective effects in rats with HAPH and that its mechanism of action is related to regulation of the Nrf2/HO-1 signaling pathway.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12906-023-03981-2.

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Most cited references 38

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Haemodynamic definitions and updated clinical classification of pulmonary hypertension

Gerald Simonneau, David Montani, David Celermajer … (2019)

Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management. Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup “pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers”, due to the specific prognostic and management of these patients, and a subgroup “PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement”, due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.

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Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis.

Ulrich Förstermann, Ning Xia, Huige Li (2017)

Major reactive oxygen species (ROS)-producing systems in vascular wall include NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide (NO) synthase. ROS at moderate concentrations have important signaling roles under physiological conditions. Excessive or sustained ROS production, however, when exceeding the available antioxidant defense systems, leads to oxidative stress. Animal studies have provided compelling evidence demonstrating the roles of vascular oxidative stress and NO in atherosclerosis. All established cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and smoking enhance ROS generation and decrease endothelial NO production. Key molecular events in atherogenesis such as oxidative modification of lipoproteins and phospholipids, endothelial cell activation, and macrophage infiltration/activation are facilitated by vascular oxidative stress and inhibited by endothelial NO. Atherosclerosis develops preferentially in vascular regions with disturbed blood flow (arches, branches, and bifurcations). The fact that these sites are associated with enhanced oxidative stress and reduced endothelial NO production is a further indication for the roles of ROS and NO in atherosclerosis. Therefore, prevention of vascular oxidative stress and improvement of endothelial NO production represent reasonable therapeutic strategies in addition to the treatment of established risk factors (hypercholesterolemia, hypertension, and diabetes mellitus).

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Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives

Marc Humbert, Christophe Guignabert, Sébastien Bonnet … (2019)

Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.

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Author and article information

Contributors

Yang Tao: 690579893@qq.com

Dilinuer Maimaitiyiming: 13999235355@163.com

Journal

Journal ID (nlm-ta): BMC Complement Med Ther

Journal ID (iso-abbrev): BMC Complement Med Ther

Title: BMC Complementary Medicine and Therapies

Publisher: BioMed Central (London )

ISSN (Electronic): 2662-7671

Publication date (Electronic): 6 May 2023

Publication date PMC-release: 6 May 2023

Publication date Collection: 2023

Volume: 23

Electronic Location Identifier: 150

Affiliations

[1 ]GRID grid.412631.3, Heart Center, , The First Affiliated Hospital of Xinjiang Medical University, ; Urumqi, 830054 China

[2 ]GRID grid.13394.3c, ISNI 0000 0004 1799 3993, College of pharmacy, , Xinjiang Medical University, ; Urumqi, 830011 China

[3 ]GRID grid.13394.3c, ISNI 0000 0004 1799 3993, Central Laboratory, , Xinjiang Medical University, ; Urumqi, 830011 China

[4 ]Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Region of PLA, Urumqi, 830000 China

Article

Publisher ID: 3981

DOI: 10.1186/s12906-023-03981-2

PMC ID: 10163731

SO-VID: 0ac0c59d-1ec9-47f5-be62-ec673272c343

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 11 February 2023

Date accepted : 27 April 2023

Funding

Funded by: the Natural Science Foundation of Xinjiang Uygur Autonomous Region

Award ID: No. 2021D01C289

Custom metadata

Keywords: terminalia bellirica (gaertn.) roxb,high-altitude pulmonary hypertension,tannins,nrf2,ho-1

Data availability:

Keywords: terminalia bellirica (gaertn.) roxb, high-altitude pulmonary hypertension, tannins, nrf2, ho-1

Protective effects of the Terminalia bellirica tannin-induced Nrf2/HO-1 signaling pathway in rats with high-altitude pulmonary hypertension

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Abstract

Background

Methods

Results

Conclusion

Supplementary Information

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Neuronal Signaling

Most cited references 38

Haemodynamic definitions and updated clinical classification of pulmonary hypertension

Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis.

Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives

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