Hydrogen therapy in cardiovascular and metabolic diseasesScientific Research


Yaxing Zhang; Sihua Tan; Jingting Xu; Tinghuai Wang

DOI: 10.1159

Published on: 09/05/2018

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


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.


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

    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.

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

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

    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.

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

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

    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.

    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.

    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.

    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.

    1. Song G, Li M, Sang H, Zhang L, Li X, Yao S, Yu Y, Zong C, Xue Y, Qin S: Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J Lipid Res 2013; 54: 1884-1893.

    1. Song G, Zong C, Zhang Z, Yu Y, Yao S, Jiao P, Tian H, Zhai L, Zhao H, Tian S, Zhang X, Wu Y, Sun X, Qin S: Molecular hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor-knockout mice. Free Radic Biol Med 2015; 87: 58-68.

    1. Hara F, Tatebe J, Watanabe I, Yamazaki J, Ikeda T, Morita T: Molecular Hydrogen Alleviates Cellular Senescence in Endothelial Cells. Circ J 2016; 80: 2037-2046.

    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.

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

    1. Sun Q, Kawamura T, Masutani K, Peng X, Sun Q, Stolz DB, Pribis JP, Billiar TR, Sun X, Bermudez CA, Toyoda Y, Nakao A: Oral intake of hydrogen-rich water inhibits intimal hyperplasia in arterialized vein grafts in rats. Cardiovasc Res 2012; 94: 144-153.

    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.

    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.

    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.

    1. Burchfield JS, Xie M, Hill JA: Pathological ventricular remodeling: mechanisms: part 1 of 2. Circulation 2013; 128: 388-400.

    1. Pedram A, Razandi M, O’Mahony F, Lubahn D, Levin ER: Estrogen receptor-beta prevents cardiac fibrosis. Mol Endocrinol 2010; 24: 2152-2165.

    1. Zhang Y, Li H: Reprogramming Interferon Regulatory Factor Signaling in Cardiometabolic Diseases. Physiology (Bethesda) 2017; 32: 210-223.

    1. Shinbo T, Kokubo K, Sato Y, Hagiri S, Hataishi R, Hirose M, Kobayashi H: Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart. Am J Physiol Heart Circ Physiol 2013; 305:H542-550.

    1. Sakai K, Cho S, Shibata I, Yoshitomi O, Maekawa T, Sumikawa K: Inhalation of hydrogen gas protects against myocardial stunning and infarction in swine. Scand Cardiovasc J 2012; 46: 183-189.

    1. Lefer DJ, Nakanishi K, Johnston WE, Vinten-Johansen J: Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs. Circulation 1993; 88: 2337-2350.

    1. Wong PS, Eiserich JP, Reddy S, Lopez CL, Cross CE, van der Vliet A: Inactivation of glutathione S-transferases by nitric oxide-derived oxidants: exploring a role for tyrosine nitration. Arch Biochem Biophys 2001; 394: 216-228.

    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.

    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.

    1. Katsumata Y, Sano F, Abe T, Tamura T, Fujisawa T, Shiraishi Y, Kohsaka S, Ueda I, Homma K, Suzuki M, Okuda S, Maekawa Y, Kobayashi E, Hori S, Sasaki J, Fukuda K, Sano M: The Effects of Hydrogen Gas Inhalation on Adverse Left Ventricular Remodeling After Percutaneous Coronary Intervention for ST-Elevated Myocardial Infarction- First Pilot Study in Humans. Circ J 2017; 81: 940-947.

    1. Hayashi T, Yamashita C, Matsumoto C, Kwak CJ, Fujii K, Hirata T, Miyamura M, Mori T, Ukimura A, Okada Y, Matsumura Y, Kitaura Y: Role of gp91phox-containing NADPH oxidase in left ventricular remodeling induced by intermittent hypoxic stress. Am J Physiol Heart Circ Physiol 2008; 294:H2197-2203.

    1. Hayashi T, Yoshioka T, Hasegawa K, Miyamura M, Mori T, Ukimura A, Matsumura Y, Ishizaka N: Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice. Am J Physiol Heart Circ Physiol 2011; 301:H1062-1069.

    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.

    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.

    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.

    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.

    1. Yu YS, Zheng H: Chronic hydrogen-rich saline treatment reduces oxidative stress and attenuates left ventricular hypertrophy in spontaneous hypertensive rats. Mol Cell Biochem 2012; 365: 233-242.

    1. Ross HJ, Law Y, Book WM, Broberg CS, Burchill L, Cecchin F, Chen JM, Delgado D, Dimopoulos K, Everitt MD, Gatzoulis M, Harris L, Hsu DT, Kuvin JT, Martin CM, Murphy AM, Singh G, Spray TL, Stout KK, American Heart Association Adults With Congenital Heart Disease Committee of the Council on Clinical C, Council on Cardiovascular Disease in the Young tCoCR, Intervention, the Council on Functional G, Translational B: Transplantation and Mechanical Circulatory Support in Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circulation 2016; 133: 802-820.

    1. Tan M, Sun X, Guo L, Su C, Sun X, Xu Z: Hydrogen as additive of HTK solution fortifies myocardial preservation in grafts with prolonged cold ischemia. Int J Cardiol 2013; 167: 383-390.

    1. Noda K, Tanaka Y, Shigemura N, Kawamura T, Wang Y, Masutani K, Sun X, Toyoda Y, Bermudez CA, Nakao A: Hydrogen-supplemented drinking water protects cardiac allografts from inflammation-associated deterioration. Transpl Int 2012; 25: 1213-1222.

    1. Nakao A, Kaczorowski DJ, Wang Y, Cardinal JS, Buchholz BM, Sugimoto R, Tobita K, Lee S, Toyoda Y, Billiar TR, McCurry KR: Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant 2010; 29: 544-553.

    1. Zhang Y, Zhang XJ, Li H: Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges. Curr Drug Targets 2017; 18: 1754-1778.

      External Resources

    1. Alberti KG, Zimmet P, Shaw J, Group IDFETFC: The metabolic syndrome–a new worldwide definition. Lancet 2005; 366: 1059-1062.

    1. Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2005; 365: 1415-1428.

    1. Li P, Liu S, Lu M, Bandyopadhyay G, Oh D, Imamura T, Johnson AMF, Sears D, Shen Z, Cui B, Kong L, Hou S, Liang X, Iovino S, Watkins SM, Ying W, Osborn O, Wollam J, Brenner M, Olefsky JM: Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Cell 2016; 167: 973-984 e912.

    1. Smith BK, Marcinko K, Desjardins EM, Lally JS, Ford RJ, Steinberg GR: Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol Endocrinol Metab 2016; 311:E730-E740.

    1. Samuel VT, Shulman GI: The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 2016; 126: 12-22.

    1. Odegaard JI, Chawla A: Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 2013; 339: 172-177.

    1. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI: Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2011; 108: 16381-16385.

    1. Bugianesi E, McCullough AJ, Marchesini G: Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005; 42: 987-1000.

    1. Fernandez-Real JM, Ricart W: Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev 2003; 24: 278-301.

    1. Kamimura N, Nishimaki K, Ohsawa I, Ohta S: Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring) 2011; 19: 1396-1403.

    1. Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N: Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr 2010; 46: 140-149.

    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.

    1. Zhang X, Liu J, Jin K, Xu H, Wang C, Zhang Z, Kong M, Zhang Z, Wang Q, Wang F: Subcutaneous injection of H2 is a novel effective treatment for type 2 diabetes. J Diabetes Investig 2017; 9: 83-90.

    1. Itoh T, Hamada N, Terazawa R, Ito M, Ohno K, Ichihara M, Nozawa Y, Ito M: Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun 2011; 411: 143-149.

    1. Chen L, Ma C, Bian Y, Li J, Wang T, Su L, Lu J: Hydrogen Treatment Protects Mice Against Chronic Pancreatitis by Restoring Regulatory T Cells Loss. Cell Physiol Biochem 2017; 44: 2005-2016.

    1. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R: H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 2008; 322: 587-590.

    1. Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, Csizmadia E, Tyagi S, Akamatsu Y, Flavell RJ, Billiar TR, Tzeng E, Bach FH, Choi AM, Soares MP: Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med 2003; 9: 183-190.

    1. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601-605.

    1. Streeter E, Ng HH, Hart JL: Hydrogen sulfide as a vasculoprotective factor. Med Gas Res 2013; 3: 9.

    1. Yang F, Zhang L, Gao Z, Sun X, Yu M, Dong S, Wu J, Zhao Y, Xu C, Zhang W, Lu F: Exogenous H2S Protects Against Diabetic Cardiomyopathy by Activating Autophagy via the AMPK/mTOR Pathway. Cell Physiol Biochem 2017; 43: 1168-1187.

    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.

    1. Luo ZL, Ren JD, Huang Z, Wang T, Xiang K, Cheng L, Tang LJ: The Role of Exogenous Hydrogen Sulfide in Free Fatty Acids Induced Inflammation in Macrophages. Cell Physiol Biochem 2017; 42: 1635-1644.

    1. Wang ZJ, Wu J, Guo W, Zhu YZ: Atherosclerosis and the Hydrogen Sulfide Signaling Pathway – Therapeutic Approaches to Disease Prevention. Cell Physiol Biochem 2017; 42: 859-875.

    1. Tang C, Li X, Du J: Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system. Curr Vasc Pharmacol 2006; 4: 17-22.

    1. Zhang YX, Wang TH: Research advances in the vascular protective effects of H2. Chinese Heart Journal 2014; 26: 348-352.

  1. Miller SL: A production of amino acids under possible primitive earth conditions. Science 1953; 117: 528-529.