Resveratrol, a New Allosteric Effector of Hemoglobin, Enhances Oxygen Supply Efficiency and Improves Adaption to Acute Severe Hypoxia

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Mar 11

PMID 36903296

Authors

Zongtang Chu

Weidan Li

Guoxing You

Yuzhi Chen

Dong Qin

Peilin Shu

Yujing Wang

Ying Wang

Lian Zhao

Hong Zhou

Affiliations

Soon will be listed here.

Abstract

Acute altitude hypoxia represents the cause of multiple adverse consequences. Current treatments are limited by side effects. Recent studies have shown the protective effects of resveratrol (RSV), but the mechanism remains unknown. To address this, the effects of RSV on the structure and function of hemoglobin of adult (HbA) were preliminarily analyzed using surface plasmon resonance (SPR) and oxygen dissociation assays (ODA). Molecular docking was conducted to specifically analyze the binding regions between RSV and HbA. The thermal stability was characterized to further validate the authenticity and effect of binding. Changes in the oxygen supply efficiency of HbA and rat RBCs incubated with RSV were detected ex vivo. The effect of RSV on the anti-hypoxic capacity under acute hypoxic conditions in vivo was evaluated. We found that RSV binds to the heme region of HbA following a concentration gradient and affects the structural stability and rate of oxygen release of HbA. RSV enhances the oxygen supply efficiency of HbA and rat RBCs ex vivo. RSV prolongs the tolerance times of mice suffering from acute asphyxia. By enhancing the oxygen supply efficiency, it alleviates the detrimental effects of acute severe hypoxia. In conclusion, RSV binds to HbA and regulates its conformation, which enhances oxygen supply efficiency and improves adaption to acute severe hypoxia.

Citing Articles

Effect of Hb conformational changes on oxygen transport physiology.

Yin Z, Li D, Guo Q, Wang R, Li W Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024; 49(3):467-475.

PMID: 38970521 PMC: 11208409. DOI: 10.11817/j.issn.1672-7347.2024.230199.

References

Tarasev M, Ferranti M, Herppich A, Hines P . GBT1118, a voxelotor analog, protects red blood cells from damage during severe hypoxia. Am J Transl Res. 2022; 14(1):240-251. PMC: 8829590. View

Woods J, Storey C, Babcock E, Malloy C . Right-shifting the oxyhemoglobin dissociation curve with RSR13: effects on high-energy phosphates and myocardial recovery after low-flow ischemia. J Cardiovasc Pharmacol. 1998; 31(3):359-63. DOI: 10.1097/00005344-199803000-00005. View

Lavrinenko I, Vashanov G, Hernandez Caceres J, Buchelnikov A, Nechipurenko Y . A New Model of Hemoglobin Oxygenation. Entropy (Basel). 2022; 24(9). PMC: 9498255. DOI: 10.3390/e24091214. View

Song T, Yang Y, Wei H, Xie X, Lu J, Zeng Q . Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation. Nucleic Acids Res. 2019; 47(12):6130-6144. PMC: 6614822. DOI: 10.1093/nar/gkz312. View

Nakagawa A, Ferrari M, Schleifer G, Cooper M, Liu C, Yu B . A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells. Mol Pharm. 2018; 15(5):1954-1963. PMC: 5942180. DOI: 10.1021/acs.molpharmaceut.8b00108. View

Jendroszek A, Malte H, Overgaard C, Beedholm K, Natarajan C, Weber R . Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose. J Exp Biol. 2018; 221(Pt 18). PMC: 6176913. DOI: 10.1242/jeb.185470. View

Deng B, Liu W, Pu L, Wang X, Duan R, Wang T . Quantitative Proteomics Reveals the Effects of Resveratrol on High-Altitude Polycythemia Treatment. Proteomics. 2020; 20(14):e1900423. DOI: 10.1002/pmic.201900423. View

Song D, Zhao M, Feng L, Wang P, Li Y, Li W . Salidroside attenuates acute lung injury via inhibition of inflammatory cytokine production. Biomed Pharmacother. 2021; 142:111949. DOI: 10.1016/j.biopha.2021.111949. View

Kassa T, Wood F, Strader M, Alayash A . Antisickling Drugs Targeting βCys93 Reduce Iron Oxidation and Oxidative Changes in Sickle Cell Hemoglobin. Front Physiol. 2019; 10:931. PMC: 6668304. DOI: 10.3389/fphys.2019.00931. View

10.

Murdoch . High life: A history of high altitude physiology and medicine . BMJ. 1999; 318(7198):1631. PMC: 1115988. DOI: 10.1136/bmj.318.7198.1631. View

11.

Li Y, Cai R, Yang J, Hendrickson T, Xiang Y, Javid B . Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity. mBio. 2021; 12(4):e0110021. PMC: 8406222. DOI: 10.1128/mBio.01100-21. View

12.

Paoli M, Liddington R, Tame J, Wilkinson A, Dodson G . Crystal structure of T state haemoglobin with oxygen bound at all four haems. J Mol Biol. 1996; 256(4):775-92. DOI: 10.1006/jmbi.1996.0124. View

13.

Alarcon de la Lastra C, Villegas I . Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res. 2005; 49(5):405-30. DOI: 10.1002/mnfr.200500022. View

14.

Ren B, Kwah M, Liu C, Ma Z, Shanmugam M, Ding L . Resveratrol for cancer therapy: Challenges and future perspectives. Cancer Lett. 2021; 515:63-72. DOI: 10.1016/j.canlet.2021.05.001. View

15.

Ivy C, Wearing O, Natarajan C, Schweizer R, Gutierrez-Pinto N, Velotta J . Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice. J Exp Biol. 2021; 225(2). PMC: 8917448. DOI: 10.1242/jeb.243595. View

16.

Yi R, Sandhu J, Zhao S, Lam G, Loganathan D, Morrissey B . Detection of efaproxiral (RSR13) and its metabolites in equine by liquid chromatography tandem mass spectrometry. J Mass Spectrom. 2014; 49(1):57-67. DOI: 10.1002/jms.3304. View

17.

Sasagawa K, Imai K, Kobayashi M . Influence of allosteric effectors and temperature on oxygen binding properties and the Bohr effect of bovine hemoglobin. Zoolog Sci. 2006; 23(6):565-72. DOI: 10.2108/zsj.23.565. View

18.

Dufu K, Patel M, Oksenberg D, Cabrales P . GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions. Clin Hemorheol Microcirc. 2018; 70(1):95-105. PMC: 6996409. DOI: 10.3233/CH-170340. View

19.

Mairbaurl H, Weber R . Oxygen transport by hemoglobin. Compr Physiol. 2013; 2(2):1463-89. DOI: 10.1002/cphy.c080113. View

20.

Schneider M, Linecker M, Fritsch R, Muehlematter U, Stocker D, Pestalozzi B . Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors. Nat Commun. 2021; 12(1):3807. PMC: 8217170. DOI: 10.1038/s41467-021-24069-w. View