H2 Mediates Cardioprotection Via Involvements of KATP Channels and Permeability Transition Pores of Mitochondria in Dogs

Yoshida, Akemi; Asanuma, Hiroshi; Sasaki, Hideyuki; Shoji, Shuichi; Yamazaki, Satoru; Asano, Yoshihiro; Shinozaki, Yoshiro; Mori, Hiromu; Shimouchi, Akito; Sano, Motoaki; Asakura, Masanori; Minamino, Tetsuo; Takashima, Seiji; Sugimachi, Masaru; Mochizuki, Naoki; Kitakaze, Masafumi

doi:10.1007/s10557-012-6381-5

Cited by 48 publications

(42 citation statements)

References 43 publications

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“…We undertook experiments in rats2 and dogs3 with Professor Shigeo Ohta from the Nippon Medical School (Tokyo, Japan) and Dr. Masafumi Kitakaze from the National Cerebral and Cardiovascular Center (Osaka, Japan), which verified that inhalation of 1–4% hydrogen gas alleviated tissue damage and reduced the infarct size. An investigator‐initiated clinical trial to assess the safety and efficacy of inhaled hydrogen gas for the prevention of reperfusion injury in patients with acute MI undergoing percutaneous coronary intervention was started at Keio University Hospital (Tokyo, Japan) in December 2011 (UMIN Clinical Trials Registry number: UMIN000006825).…”

Section: Clinical Evidencementioning

confidence: 86%

Promising novel therapy with hydrogen gas for emergency and critical care medicine

Sano

Suzuki

Homma

et al. 2017

Acute Medicine & Surgery

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It has been reported that hydrogen gas exerts a therapeutic effect in a wide range of disease conditions, from acute illness such as ischemia–reperfusion injury, shock, and damage healing to chronic illness such as metabolic syndrome, rheumatoid arthritis, and neurodegenerative diseases. Antioxidant and anti‐inflammatory properties of hydrogen gas have been proposed, but the molecular target of hydrogen gas has not been identified. We established the Center for Molecular Hydrogen Medicine to promote non‐clinical and clinical research on the medical use of hydrogen gas through industry–university collaboration and to obtain regulatory approval of hydrogen gas and hydrogen medical devices (http://www.karc.keio.ac.jp/center/center-55.html). Studies undertaken by the Center have suggested possible therapeutic effects of hydrogen gas in relation to various aspects of emergency and critical care medicine, including acute myocardial infarction, cardiopulmonary arrest syndrome, contrast‐induced acute kidney injury, and hemorrhagic shock.

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Section: Clinical Evidencementioning

confidence: 86%

Promising novel therapy with hydrogen gas for emergency and critical care medicine

Sano

Suzuki

Homma

et al. 2017

Acute Medicine & Surgery

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“…37 Inhaled H 2 acts rapidly; therefore, it may also be suitable as a defense against acute oxidative stress elicited by ischemia/ reperfusion. 1,4,11 Inhaled H 2 at therapeutic doses has no adverse effects on the saturation level of arterial oxygen (Spo 2 ) or hemodynamic parameters, including blood pressure, heart rate, and left ventricular pressure. 4 H 2 may accumulate in the lipid phase more than in the aqueous phase, especially in unsaturated lipid regions, which are the major target of the radical chain reaction.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

et al. 2014

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Background-We have previously shown that hydrogen (H 2 ) inhalation, begun at the start of hyperoxic cardiopulmonary resuscitation, significantly improves brain and cardiac function in a rat model of cardiac arrest. Here, we examine the effectiveness of this therapeutic approach when H 2 inhalation is begun on the return of spontaneous circulation (ROSC) under normoxic conditions, either alone or in combination with targeted temperature management (TTM). Methods and Results-Rats were subjected to 6 minutes of ventricular fibrillation cardiac arrest followed by cardiopulmonary resuscitation. Five minutes after achieving ROSC, post-cardiac arrest rats were randomized into 4 groups: mechanically ventilated with 26% O 2 and normothermia (control); mechanically ventilated with 26% O 2 , 1.3% H 2 , and normothermia (H 2 ); mechanically ventilated with 26% O 2 and TTM (TTM); and mechanically ventilated with 26% O 2 , 1.3% H 2 , and TTM (TTM+H 2 ). Animal survival rate at 7 days after ROSC was 38.4% in the control group, 71.4% in the H 2 and TTM groups, and 85.7% in the TTM+H 2 group. Combined therapy of TTM and H 2 inhalation was superior to TTM alone in terms of neurological deficit scores at 24, 48, and 72 hours after ROSC, and motor activity at 7 days after ROSC. Neuronal degeneration and microglial activation in a vulnerable brain region was suppressed by both TTM alone and H 2 inhalation alone, with the combined therapy of TTM and H 2 inhalation being most effective. Conclusions-H 2 inhalation was beneficial when begun after ROSC, even when delivered in the absence of hyperoxia.Combined TTM and H 2 inhalation was more effective than TTM alone. (Circulation. 2014;130:2173-2180.)

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“…Apoptotic cells were identified using a TUNELbased in situ apoptosis detection kit (S7100; Millipore) as described previously (53). After a 30-min treatment with 0.3% H 2O2-methanol at room temperature, tissue sections were incubated with the TUNEL reaction mixture, rinsed, and counterstained with 1% methyl green solution.…”

Section: Methodsmentioning

confidence: 99%

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

Ihara

Asanuma

Yamazaki

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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zuki N, Kitakaze M. An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 308: H1287-H1297, 2015. First published March 7, 2015; doi:10.1152/ajpheart.00835.2014.-Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1-and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 Ϯ 2.5% to 17.1 Ϯ 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3␤, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor-and CREB-dependent signaling pathways. dipeptidyl peptidase 4 inhibitor; ischemia-reperfusion injury; myocardial infarction; cardioprotection; adenosine GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is mostly known as a potent antihyperglycemic hormone secreted by intestinal cells to stimulate glucose-dependent insulin secretion from pancreatic beta cells. Once in circulation, GLP-1 is rapidly metabolized by dipeptidyl peptidase 4 (DPP4). Therefore, GLP-1 analogs and DPP4 inhibitors are commonly prescribed for the treatment of diabetes mellitus (6, 11). DPP4 inhibitors also exert extrapancreatic effects in the brain, stomach, and heart (39). However, the mechanisms by which they mediate these effects remain largely unknown. Several reports showed that DPP4 inhibitors limit the infarct size after ischemia-reperfusion in the heart (15, 51), but the extent of their beneficial effects remains controversial (7,52). Recently, several reports have indicated that DPP4 forms a complex with adenosin...

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H2 Mediates Cardioprotection Via Involvements of KATP Channels and Permeability Transition Pores of Mitochondria in Dogs

Abstract: Inhalation of H(2) gas reduces infarct size in canine hearts via opening of mitochondrial K(ATP) channels followed by inhibition of mPTP. H(2) gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.

Cited by 48 publications

References 43 publications

Promising novel therapy with hydrogen gas for emergency and critical care medicine

Promising novel therapy with hydrogen gas for emergency and critical care medicine

Hydrogen Inhalation During Normoxic Resuscitation Improves Neurological Outcome in a Rat Model of Cardiac Arrest Independently of Targeted Temperature Management

An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury

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