Hydrogen therapy in cardiovascular and metabolic diseasesScientific Research

Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside

Zhang Y.a · Tan S.a · Xu J.c · Wang T.a,b,c
Author affiliations

 

Corresponding Author

Cell Physiol Biochem 2018;47:1–10
https://doi.org/10.1159/000489737

Abstract

Hydrogen (H2) is colorless, odorless, and the lightest of all gas molecules. Research over the past decade has shown that H2 is extremely important in regulating cardiovascular homeostasis and metabolic activity. In animal models or clinical trials, delivery of H2 through various strategies ameliorates cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia, or cardiac injury from cardiac transplantation , obesity and diabetes. The purpose of this review is to summarize the physical and chemical properties of H2 and the function of H2, with a focus on the therapeutic potential and molecular mechanisms of the aforementioned diseases. We hope this review sheds light on the future prospects of H2-based therapies for cardiometabolic diseases.

© 2018 Author. Published by S. Karger AG, Basel

Disclosure Statement

No conflict of interests exists.

References

    1. Ohta S: Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des 2011; 17: 2241-2252.

      External Resources

    1. Iida A, Nosaka N, Yumoto T, Knaup E, Naito H, Nishiyama C, Yamakawa Y, Tsukahara K, Terado M, Sato K, Ugawa T, Nakao A: The Clinical Application of Hydrogen as a Medical Treatment. Acta Med Okayama 2016; 70: 331-337.

      External Resources

    1. Olson JW, Maier RJ: Molecular hydrogen as an energy source for Helicobacter pylori. Science 2002; 298: 1788-1790.

      External Resources

    1. Kajiya M, Sato K, Silva MJ, Ouhara K, Do PM, Shanmugam KT, Kawai T: Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun 2009; 386: 316-321.

      External Resources

    1. Wolf PG, Biswas A, Morales SE, Greening C, Gaskins HR: H2 metabolism is widespread and diverse among human colonic microbes. Gut Microbes 2016; 7: 235-245.

      External Resources

    1. Vignais PM, Colbeau A: Molecular biology of microbial hydrogenases. Curr Issues Mol Biol 2004; 6: 159-188.

      External Resources

    1. Maier L, Vyas R, Cordova CD, Lindsay H, Schmidt TS, Brugiroux S, Periaswamy B, Bauer R, Sturm A, Schreiber F, von Mering C, Robinson MD, Stecher B, Hardt WD: Microbiota-derived hydrogen fuels Salmonella typhimurium invasion of the gut ecosystem. Cell Host Microbe 2013; 14: 641-651.

      External Resources

    1. Ohta S: Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther 2014; 144: 1-11.

      External Resources

    1. Dixon BJ, Tang J, Zhang JH: The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res 2013; 3: 10.

      External Resources

    1. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13: 688-694.

      External Resources

    1. Huang CS, Kawamura T, Toyoda Y, Nakao A: Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res 2010; 44: 971-982.

      External Resources

    1. Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, Endo J, Katayama T, Kawamura A, Kohsaka S, Makino S, Ohta S, Ogawa S, Fukuda K: Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 2008; 373: 30-35.

      External Resources

    1. Zhang Y, Xu J, Long Z, Wang C, Wang L, Sun P, Li P, Wang T: Hydrogen (H2) Inhibits Isoproterenol-Induced Cardiac Hypertrophy via Antioxidative Pathways. Frontiers in Pharmacology 2016; 7: 392.

      External Resources

    1. Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X: Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int J Cardiol 2011; 148: 91-95.

      External Resources

    1. Sun Q, Kang Z, Cai J, Liu W, Liu Y, Zhang JH, Denoble PJ, Tao H, Sun X: Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood) 2009; 234: 1212-1219.

      External Resources

    1. Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S: Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun 2008; 377: 1195-1198.

      External Resources

    1. Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nakamura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T: Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res 2008; 28: 137-143.

      External Resources

    1. Noda K, Shigemura N, Tanaka Y, Kawamura T, Hyun Lim S, Kokubo K, Billiar TR, Bermudez CA, Kobayashi H, Nakao A: A novel method of preserving cardiac grafts using a hydrogen-rich water bath. J Heart Lung Transplant 2013; 32: 241-250.

      External Resources

    1. Suzuki Y, Sano M, Hayashida K, Ohsawa I, Ohta S, Fukuda K: Are the effects of alpha-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett 2009; 583: 2157-2159.

      External Resources

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      External Resources

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    1. Ekuni D, Tomofuji T, Endo Y, Kasuyama K, Irie K, Azuma T, Tamaki N, Mizutani S, Kojima A, Morita M: Hydrogen-rich water prevents lipid deposition in the descending aorta in a rat periodontitis model. Arch Oral Biol 2012; 57: 1615-1622.

      External Resources

    1. Song G, Tian H, Liu J, Zhang H, Sun X, Qin S: H2 inhibits TNF-alpha-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor kappaB activation in endothelial cells. Biotechnol Lett 2011; 33: 1715-1722.

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    External Resources

DOI: 10.1159

Published on: 20180905

Authors:

Yaxing Zhang; Sihua Tan; Jingting Xu; Tinghuai Wang

Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside

Zhang Y.a · Tan S.a · Xu J.c · Wang T.a,b,c
Author affiliations

 

Corresponding Author

Cell Physiol Biochem 2018;47:1–10
https://doi.org/10.1159/000489737

Abstract

Hydrogen (H2) is colorless, odorless, and the lightest of all gas molecules. Research over the past decade has shown that H2 is extremely important in regulating cardiovascular homeostasis and metabolic activity. In animal models or clinical trials, delivery of H2 through various strategies ameliorates cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia, or cardiac injury from cardiac transplantation , obesity and diabetes. The purpose of this review is to summarize the physical and chemical properties of H2 and the function of H2, with a focus on the therapeutic potential and molecular mechanisms of the aforementioned diseases. We hope this review sheds light on the future prospects of H2-based therapies for cardiometabolic diseases.

© 2018 Author. Published by S. Karger AG, Basel

Disclosure Statement

No conflict of interests exists.

References

    1. Ohta S: Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des 2011; 17: 2241-2252.

      External Resources

    1. Iida A, Nosaka N, Yumoto T, Knaup E, Naito H, Nishiyama C, Yamakawa Y, Tsukahara K, Terado M, Sato K, Ugawa T, Nakao A: The Clinical Application of Hydrogen as a Medical Treatment. Acta Med Okayama 2016; 70: 331-337.

      External Resources

    1. Olson JW, Maier RJ: Molecular hydrogen as an energy source for Helicobacter pylori. Science 2002; 298: 1788-1790.

      External Resources

    1. Kajiya M, Sato K, Silva MJ, Ouhara K, Do PM, Shanmugam KT, Kawai T: Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun 2009; 386: 316-321.

      External Resources

    1. Wolf PG, Biswas A, Morales SE, Greening C, Gaskins HR: H2 metabolism is widespread and diverse among human colonic microbes. Gut Microbes 2016; 7: 235-245.

      External Resources

    1. Vignais PM, Colbeau A: Molecular biology of microbial hydrogenases. Curr Issues Mol Biol 2004; 6: 159-188.

      External Resources

    1. Maier L, Vyas R, Cordova CD, Lindsay H, Schmidt TS, Brugiroux S, Periaswamy B, Bauer R, Sturm A, Schreiber F, von Mering C, Robinson MD, Stecher B, Hardt WD: Microbiota-derived hydrogen fuels Salmonella typhimurium invasion of the gut ecosystem. Cell Host Microbe 2013; 14: 641-651.

      External Resources

    1. Ohta S: Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther 2014; 144: 1-11.

      External Resources

    1. Dixon BJ, Tang J, Zhang JH: The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res 2013; 3: 10.

      External Resources

    1. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13: 688-694.

      External Resources

    1. Huang CS, Kawamura T, Toyoda Y, Nakao A: Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res 2010; 44: 971-982.

      External Resources

    1. Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, Endo J, Katayama T, Kawamura A, Kohsaka S, Makino S, Ohta S, Ogawa S, Fukuda K: Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun 2008; 373: 30-35.

      External Resources

    1. Zhang Y, Xu J, Long Z, Wang C, Wang L, Sun P, Li P, Wang T: Hydrogen (H2) Inhibits Isoproterenol-Induced Cardiac Hypertrophy via Antioxidative Pathways. Frontiers in Pharmacology 2016; 7: 392.

      External Resources

    1. Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X: Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int J Cardiol 2011; 148: 91-95.

      External Resources

    1. Sun Q, Kang Z, Cai J, Liu W, Liu Y, Zhang JH, Denoble PJ, Tao H, Sun X: Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood) 2009; 234: 1212-1219.

      External Resources

    1. Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S: Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun 2008; 377: 1195-1198.

      External Resources

    1. Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nakamura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T: Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res 2008; 28: 137-143.

      External Resources

    1. Noda K, Shigemura N, Tanaka Y, Kawamura T, Hyun Lim S, Kokubo K, Billiar TR, Bermudez CA, Kobayashi H, Nakao A: A novel method of preserving cardiac grafts using a hydrogen-rich water bath. J Heart Lung Transplant 2013; 32: 241-250.

      External Resources

    1. Suzuki Y, Sano M, Hayashida K, Ohsawa I, Ohta S, Fukuda K: Are the effects of alpha-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett 2009; 583: 2157-2159.

      External Resources

    1. Gibbons GH, Dzau VJ: The emerging concept of vascular remodeling. N Engl J Med 1994; 330: 1431-1438.

      External Resources

    1. Majesky MW: Adventitia and perivascular cells. Arterioscler Thromb Vasc Biol 2015; 35:e31-35.

      External Resources

    1. Ekuni D, Tomofuji T, Endo Y, Kasuyama K, Irie K, Azuma T, Tamaki N, Mizutani S, Kojima A, Morita M: Hydrogen-rich water prevents lipid deposition in the descending aorta in a rat periodontitis model. Arch Oral Biol 2012; 57: 1615-1622.

      External Resources

    1. Song G, Tian H, Liu J, Zhang H, Sun X, Qin S: H2 inhibits TNF-alpha-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor kappaB activation in endothelial cells. Biotechnol Lett 2011; 33: 1715-1722.

      External Resources

    1. Song G, Tian H, Qin S, Sun X, Yao S, Zong C, Luo Y, Liu J, Yu Y, Sang H, Wang X: Hydrogen decreases athero-susceptibility in apolipoprotein B-containing lipoproteins and aorta of apolipoprotein E knockout mice. Atherosclerosis 2012; 221: 55-65.

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    1. Zong C, Song G, Yao S, Li L, Yu Y, Feng L, Guo S, Luo T, Qin S: Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters. Metabolism 2012; 61: 794-800.

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    1. Zhang YX, Xu JT, You XC, Wang C, Zhou KW, Li P, Sun P, Wang L, Wang TH: Inhibitory Effects of Hydrogen on Proliferation and Migration of Vascular Smooth Muscle Cells via Down-Regulation of Mitogen/Activated Protein Kinase and Ezrin-Radixin-Moesin Signaling Pathways. Chin J Physiol 2016; 59: 46-55.

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    1. Zheng H, Yu YS: Chronic hydrogen-rich saline treatment attenuates vascular dysfunction in spontaneous hypertensive rats. Biochem Pharmacol 2012; 83: 1269-1277.

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    1. Qin ZX, Yu P, Qian DH, Song MB, Tan H, Yu Y, Li W, Wang H, Liu J, Wang Q, Sun XJ, Jiang H, Zhu JK, Lu W, Huang L: Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atherosclerosis 2012; 220: 343-350.

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    1. Chen Y, Jiang J, Miao H, Chen X, Sun X, Li Y: Hydrogen-rich saline attenuates vascular smooth muscle cell proliferation and neointimal hyperplasia by inhibiting reactive oxygen species production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways. Int J Mol Med 2013; 31: 597-606.

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    1. Chen K, Wang N, Diao Y, Dong W, Sun Y, Liu L, Wu X: Hydrogen-Rich Saline Attenuates Brain Injury Induced by Cardiopulmonary Bypass and Inhibits Microvascular Endothelial Cell Apoptosis Via the PI3K/Akt/ GSK3beta Signaling Pathway in Rats. Cell Physiol Biochem 2017; 43: 1634-1647.

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    1. He Y, Zhang B, Chen Y, Jin Q, Wu J, Yan F, Zheng H: Image-Guided Hydrogen Gas Delivery for Protection from Myocardial Ischemia-Reperfusion Injury via Microbubbles. ACS Appl Mater Interfaces 2017; 9: 21190-21199.

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    1. Zalesak M, Kura B, Graban J, Ledvenyiova-Farkasova V, Slezak J, Ravingerova T: Molecular hydrogen potentiates beneficial anti-infarct effect of hypoxic postconditioning in isolated rat hearts: Novel cardioprotective intervention. Can J Physiol Pharmacol 2017; 95: 888-893.

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    1. Kato R, Nomura A, Sakamoto A, Yasuda Y, Amatani K, Nagai S, Sen Y, Ijiri Y, Okada Y, Yamaguchi T, Izumi Y, Yoshiyama M, Tanaka K, Hayashi T: Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters. Am J Physiol Heart Circ Physiol 2014; 307:H1626-1633.

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    1. Zhang Y, Long Z, Xu J, Tan S, Zhang N, Li A, Wang L, Wang T: Hydrogen inhibits isoproterenolinduced autophagy in cardiomyocytes in vitro and in vivo. Mol Med Rep 2017; 16: 8253-8258.

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    1. Gao Y, Yang H, Chi J, Xu Q, Zhao L, Yang W, Liu W, Yang W: Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy. Cell Physiol Biochem 2017; 43: 1503-1514.

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    1. Jing L, Wang Y, Zhao XM, Zhao B, Han JJ, Qin SC, Sun XJ: Cardioprotective Effect of Hydrogen-rich Saline on Isoproterenol-induced Myocardial Infarction in Rats. Heart Lung Circ 2015; 24: 602-610.

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    1. Song G, Lin Q, Zhao H, Liu M, Ye F, Sun Y, Yu Y, Guo S, Jiao P, Wu Y, Ding G, Xiao Q, Qin S: Hydrogen Activates ATP-Binding Cassette Transporter A1-Dependent Efflux Ex Vivo and Improves High-Density Lipoprotein Function in Patients With Hypercholesterolemia: A Double-Blinded, Randomized, and Placebo-Controlled Trial. J Clin Endocrinol Metab 2015; 100: 2724-2733.

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    1. Ke X, Zou J, Hu Q, Wang X, Hu C, Yang R, Liang J, Shu X, Nie R, Peng C: Hydrogen Sulfide-Preconditioning of Human Endothelial Progenitor Cells Transplantation Improves Re-Endothelialization in Nude Mice with Carotid Artery Injury. Cell Physiol Biochem 2017; 43: 308-319.

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