Differential temporal inhibition of mitochondrial fission by Mdivi-1 exerts effective cardioprotection in cardiac ischemia/reperfusion injury

2018 ◽  
Vol 132 (15) ◽  
pp. 1669-1683 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Lv Function ◽  
Male Wistar Rats ◽  
Group A

Altered cardiac mitochondrial dynamics with excessive fission is a predominant cause of cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although pre-ischemic inhibition of mitochondrial fission has been shown to improve cardiac function in I/R injury, the effects of this inhibitor given at different time-points during cardiac I/R injury are unknown. Fifty male Wistar rats were subjected to sham and cardiac I/R injury. For cardiac I/R injury, rats were randomly divided into pre-ischemia, during-ischemia, and upon onset of reperfusion group. A mitochondrial fission inhibitor, Mdivi-1 (mitochondrial division inhibitor 1) (1.2 mg/kg) was used. During I/R protocols, the left ventricular (LV) function, arrhythmia score, and mortality rate were determined. Then, the heart was removed to determine infarct size, mitochondrial function, mitochondrial dynamics, and apoptosis. Our results showed that Mdivi-1 given prior to ischemia, exerted the highest level of cardioprotection quantitated through the attenuated incidence of arrhythmia, reduced infarct size, improved cardiac mitochondrial function and fragmentation, and decreased cardiac apoptosis, leading to preserved LV function during I/R injury. Mdivi-1 administered during ischemia and upon the onset of reperfusion also improved cardiac mitochondrial function and LV function, but at a lower efficacy than when it was given prior to ischemia. Taken together, mitochondrial fission inhibition after myocardial ischemic insults still exerts cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings indicate its potential clinical usefulness.

Balancing mitochondrial dynamics via increasing mitochondrial fusion attenuates infarct size and left ventricular dysfunction in rats with cardiac ischemia/reperfusion injury

2019 ◽  
Vol 133 (3) ◽  
pp. 497-513 ◽  
Author(s):  
Chayodom Maneechote ◽  
Siripong Palee ◽  
Sasiwan Kerdphoo ◽  
Thidarat Jaiwongkam ◽  
Siriporn C. Chattipakorn ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Mitochondrial Fusion ◽  
Time Points

Abstract An uncontrolled balance of mitochondrial dynamics has been shown to contribute to cardiac dysfunction during ischemia/reperfusion (I/R) injury. Although inhibition of mitochondrial fission could ameliorate cardiac dysfunction, modulation of mitochondrial fusion by giving a fusion promoter at different time-points during cardiac I/R injury has never been investigated. We hypothesized that giving of a mitochondrial fusion promoter at different time-points exerts cardioprotection with different levels of efficacy in rats with cardiac I/R injury. Forty male Wistar rats were subjected to a 30-min ischemia by coronary occlusion, followed by a 120-min reperfusion. The rats were then randomly divided into control and three treated groups: pre-ischemia, during-ischemia, and onset of reperfusion. A pharmacological mitochondrial fusion promoter-M1 (2 mg/kg) was used for intervention. Reduced mitochondrial fusion protein was observed after cardiac I/R injury. M1 administered prior to ischemia exerted the highest level of cardioprotection by improving both cardiac mitochondrial function and dynamics regulation, attenuating incidence of arrhythmia, reducing infarct size and cardiac apoptosis, which led to the preservation of cardiac function and decreased mortality. M1 given during ischemia and on the onset of reperfusion also exerted cardioprotection, but with a lower efficacy than when given at the pre-ischemia time-point. Attenuating a reduction in mitochondrial fusion proteins during myocardial ischemia and at the onset of reperfusion exerted cardioprotection by attenuating mitochondrial dysfunction and dynamic imbalance, thus reducing infarct size and improving cardiac function. These findings indicate that it could be a promising intervention with the potential to afford cardioprotection in the clinical setting of acute myocardial infarction.

scholarly journals Metformin exerts cardioprotection via attenuating mitochondrial fission in cardiac ischaemia-reperfusion injury in rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Palee ◽  
L Higgins ◽  
T Leech ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Control Group ◽  
Lv Function ◽  
Funding Source ◽  
Cardiac Ischaemia

Abstract Background Cardiac ischemia/reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further cardiomyocytes death and impaired cardiac contractility. Although metformin has been shown to exert cardioprotection in addition to glycemic control, its effect on cardiac I/R injury are still controversy, and the comparative doses of metformin in cardiac I/R injury have never been investigated. Purpose We hypothesized that metformin given acutely prior to cardiac ischaemia exerts cardioprotection in rats with cardiac I/R injury via attenuating cardiac mitochondrial dysfunction, leading to improved left ventricular (LV) function. Methods Forty Male Wistar rats were subjected to cardiac I/R injury. Four treatment groups were investigated. The first group received saline as a control group. The second to the fourth groups received metformin at 100, 200, and 400 mg/kg intravenously, respectively. During the I/R protocols, the LV function, arrhythmia score, and mortality rate were determined. At the end, the hearts were rapidly removed to determine infarct size, cardiac mitochondrial function, cardiac mitochondrial dynamics, and cardiac apoptosis. Results Metformin 200 mg/kg exerted the highest level of cardioprotection through the attenuated incidence of arrhythmia, decreased infarct size (Fig. 1), improved cardiac mitochondrial function, and decreased mitochondrial fission (Fig. 1) and cardiac apoptotic markers, leading to improved cardiac function during I/R injury. Although Metformin at all doses effectively decreased infarct size, improved cardiac mitochondrial function and LV function, Metformin at 200 mg/kg exerted the best efficacy (Fig. 1). Conclusions Metformin exerts cardioprotection by attenuating mitochondrial dysfunction and decreased mitochondrial fission, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings also indicate the potential biphasic effects of metformin on infarct size which are dose-dependent. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency Thailand (NC), and Thailand Research Fund (SCC)

scholarly journals Dynamin-Related Protein 1 Deficiency Promotes Recovery from AKI

2017 ◽  
Vol 29 (1) ◽  
pp. 194-206 ◽  
Author(s):  
Heather M. Perry ◽  
Liping Huang ◽  
Rebecca J. Wilson ◽  
Amandeep Bajwa ◽  
Hiromi Sesaki ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Related Protein

The proximal tubule epithelium relies on mitochondrial function for energy, rendering the kidney highly susceptible to ischemic AKI. Dynamin-related protein 1 (DRP1), a mediator of mitochondrial fission, regulates mitochondrial function; however, the cell-specific and temporal role of DRP1 in AKI in vivo is unknown. Using genetic murine models, we found that proximal tubule–specific deletion of Drp1 prevented the renal ischemia-reperfusion–induced kidney injury, inflammation, and programmed cell death observed in wild-type mice and promoted epithelial recovery, which associated with activation of the renoprotective β-hydroxybutyrate signaling pathway. Loss of DRP1 preserved mitochondrial structure and reduced oxidative stress in injured kidneys. Lastly, proximal tubule deletion of DRP1 after ischemia-reperfusion injury attenuated progressive kidney injury and fibrosis. These results implicate DRP1 and mitochondrial dynamics as an important mediator of AKI and progression to fibrosis and suggest that DRP1 may serve as a therapeutic target for AKI.

scholarly journals Environmentally persistent free radicals compromise left ventricular function during ischemia/reperfusion injury

2015 ◽  
Vol 308 (9) ◽  
pp. H998-H1006 ◽  
Author(s):  
Brendan R. Burn ◽  
Kurt J. Varner
Keyword(s):  
Free Radicals ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Halogenated Hydrocarbons ◽  
Lv Function ◽  
Stroke Work

Increases in airborne particulate matter (PM) are linked to increased mortality from myocardial ischemia. PM contains environmentally persistent free radicals (EPFRs) that form as halogenated hydrocarbons chemisorb to transition metal oxide-coated particles, and are capable of sustained redox cycling. We hypothesized that exposure to the EPFR DCB230 would increase cardiac vulnerability to subsequent myocardial ischemia-reperfusion (MI/R) injury. Rats were exposed to DCB230 or vehicle via nose-only inhalation (230 μg max/day) over 30 min/day for 7 days. MI/R or sham MI/R (sham) was initiated 24 h after the final exposure. Following 1 or 7 days of reperfusion, left ventricular (LV) function was assessed and infarct size measured. In vehicle-exposed rats, MI/R injury did not significantly reduce cardiac output (CO), stroke volume (SV), stroke work (SW), end-diastolic volume (EDV), or end-systolic volume (ESV) after 1 day of reperfusion, despite significant reductions in end-systolic pressure (ESP). Preload-recruitable SW (PRSW; contractility) was elevated, presumably to maintain LV function. MI/R 1-day rats exposed to DCB230 also had similarly reduced ESP. Compared with vehicle controls, CO, SV, and SW were significantly reduced in DCB230-exposed MI/R 1-day rats; moreover, PRSW did not increase. DCB230’s effects on LV function dissipated within 8 days of exposure. These data show that inhalation of EPFRs can exacerbate the deficits in LV function produced by subsequent MI/R injury. Infarct size was not different between the MI/R groups. We conclude that inhalation of EPFRs can compromise cardiac function during MI/R injury and may help to explain the link between PM and MI/R-related mortality.

Cardiopreventive effects of mitochondrial dynamics modulators in pre-diabetic rats subjected to cardiac ischaemia-reperfusion injury

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Maneechote ◽  
S Palee ◽  
T Jaiwongkam ◽  
S Kerdphoo ◽  
S.C Chattipakorn ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Function ◽  
Chronic Treatment ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Diabetic Rats ◽  
Mitochondrial Fusion ◽  
Lv Function ◽  
Funding Source ◽  
Ischaemia Reperfusion

Abstract Background Chronic exposure to a high-fat diet (HFD) consumption causes alteration of cardiac mitochondrial dynamics and function, leading to the abnormal left ventricular (LV) function. Since excessive mitochondrial fission and reduced mitochondrial fusion are correlated with both obesity and myocardial ischaemia, targeting mitochondrial fission and fusion could be an effective cardioprotective strategy. We previously showed that acute inhibition of mitochondrial fission and promotion of mitochondrial fusion exerted cardioprotection in obese rats. However, the chronic treatment with mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) in pre-diabetic rats subjected to cardiac ischaemia-reperfusion (I/R) injury has never been investigated. Purpose We investigated the cardiopreventive effects of chronic Mdivi-1 and M1 treatment in pre-diabetic rats with cardiac I/R injury on infarct size, mitochondrial function, and LV contractility. Methods Wistar rats (n=32, male) were fed with HFD for 12 weeks, then randomly divided into: 1) HFV (Vehicle, 0.1% DMSO), 2) HFMdivi1 (Mdivi-1, 1.2 mg/kg), and 3) HFM1 (M1, 2 mg/kg) with intraperitoneal injection. After 2 weeks of drugs administration, all rats underwent 30 min of left anterior descending coronary artery occlusion followed by reperfusion for 120 min. LV function was monitored throughout the experiment. At the end, the heart was removed to determine infarct size and mitochondrial function. Results Chronic treatment with Mdivi-1 and M1 similarly showed a decrease in mitochondrial reactive oxygen species and infarct size, leading to an improvement in LV function in HFD rats, as indicated by increased ejection fraction, when compared to HFV rats (Figure). Conclusion Mitochondrial fission inhibitor and fusion promoter exerted similar efficacy in protecting pre-diabetic rat hearts against cardiac I/R injury through attenuating mitochondrial dysfunction, reducing infarct size and increasing LV contractility. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science and Technology Development Agency Thailand

Abstract 2320: Long Acting Erectile Dysfunction Drug Tadalafil Limits Myocardial Ischemia/Reperfusion Injury and Preserves Left Ventricular Function through Protein Kinase G Dependent Pathway

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Fadi N Salloum ◽  
Ramzi A Ockaili ◽  
Antonio Abbate ◽  
Nicholas N Hoke ◽  
Vinh Q Chau ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Corpus Cavernosum ◽  
Coronary Artery Occlusion ◽  
Left Ventricular ◽  
Therapeutic Modality ◽  
Lv Function ◽  
Long Acting

Tadalafil (TAD) is a novel long acting inhibitor of phosphodiesterase-5, which enhances erectile function in men through accumulation of cGMP in the corpus cavernosum. Since cGMP-dependent protein kinase (PKG) signaling plays a key role in cardioprotection, we hypothesized that TAD would limit myocardial infarction (MI) following ischemia/reperfusion (I/R) through a mechanism involving PKG. Additionally, we contemplated that TAD would preserve left ventricular (LV) function following 30 min ischemia and 24 hr reperfusion. TAD (1 mg/kg, ip) or 10% DMSO (vehicle) was administered in ICR mice 1 hr prior to 30 min of regional ischemia by coronary artery occlusion followed by 24 hr reperfusion. In another subset of mice, KT5823 (KT), a specific PKG inhibitor (1 mg/kg, ip), was administered 10 min before TAD or 10% DMSO. Infarct size was measured at the end of reperfusion using TTC and LV function was assessed using transthoracic echocardiography. Infarct size was reduced in TAD-treated mice as compared to controls. KT abolished TAD-induced protection and KT alone had no effect on infarct size in controls (Figure ). All groups did not present with significant LV dilatation at 24 hr post infarction. However, TAD preserved fractional shortening (FS:31 ± 1.5%) as compared to control mice (FS: 22 ± 4.8%, P ± 0.05). Baseline FS was 44 ± 1.7%. KT abrogated the preservation of LV function with TAD by a marked decline in FS to 17 ± 1%. TAD is a powerful cardioprotective agent which limits MI and preserves LV function through activating PKG. Therefore, this drug may be a useful therapeutic modality to suppress I/R injury in patients with cardiovascular disease.

Cardioprotection of electroacupuncture against myocardial ischemia-reperfusion injury by modulation of cardiac norepinephrine release

2012 ◽  
Vol 302 (9) ◽  
pp. H1818-H1825 ◽  
Author(s):  
Wei Zhou ◽  
Yoshihiro Ko ◽  
Peyman Benharash ◽  
Kentaro Yamakawa ◽  
Sunny Patel ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sham Acupuncture ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardioprotective Effects ◽  
Myocardial Ischemia Reperfusion

Augmentation of cardiac sympathetic tone during myocardial ischemia has been shown to increase myocardial O2 demand and infarct size as well as induce arrhythmias. We have previously demonstrated that electroacupuncture (EA) inhibits the visceral sympathoexcitatory cardiovascular reflex. The purpose of this study was to determine the effects of EA on left ventricular (LV) function, O2 demand, infarct size, arrhythmogenesis, and in vivo cardiac norepinephrine (NE) release in a myocardial ischemia-reperfusion model. Anesthetized rabbits ( n = 36) underwent 30 min of left anterior descending coronary artery occlusion followed by 90 min of reperfusion. We evaluated myocardial O2 demand, infarct size, ventricular arrhythmias, and myocardial NE release using microdialysis under the following experimental conditions: 1) untreated, 2) EA at P5–6 acupoints, 3) sham acupuncture, 4) EA with pretreatment with naloxone (a nonselective opioid receptor antagonist), 5) EA with pretreatment with chelerythrine (a nonselective PKC inhibitor), and 6) EA with pretreatment with both naloxone and chelerythrine. Compared with the untreated and sham acupuncture groups, EA resulted in decreased O2 demand, myocardial NE concentration, and infarct size. Furthermore, the degree of ST segment elevation and severity of LV dysfunction and ventricular arrhythmias were all significantly decreased ( P < 0.05). The cardioprotective effects of EA were partially blocked by pretreatment with naloxone or chelerythrine alone and completely blocked by pretreatment with both naloxone and chelerythrine. These results suggest that the cardioprotective effects of EA against myocardial ischemia-reperfusion are mediated through inhibition of the cardiac sympathetic nervous system as well as opioid and PKC-dependent pathways.

Abstract 14708: Temporal Relationship Between Erythropoietin Administration and Mitochondrial Dysfunction in Cardiac Ischemia/reperfusion Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Juthipong Benjanuwattra ◽  
Nattayaporn Apaijai ◽  
Titikorn Chunchai ◽  
Siriporn Chattipakorn ◽  
Busarin Arunsak ◽  
...  
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lv Function ◽  
Time Points ◽  
Lv Dysfunction ◽  
Male Wistar Rats ◽  
Cellular Hypoxia ◽  
Rapid Restoration

Introduction: Acute myocardial infarction remains a leading cause of mortality. Rapid restoration of coronary blood flow is the cornerstone of treatment. Paradoxically, it leads to a condition known as ischemia/reperfusion (I/R) injury which precipitates more injuries to the heart. Erythropoietin (EPO), a hormone produced by the kidneys in response to cellular hypoxia, reportedly provides cardioprotection following cardiac I/R injury in many preclinical experiments. Unfortunately, clinical trials failed to demonstrate cardioprotection when EPO was given after reperfusion. Therefore, we aim to determine the temporal influences on administering EPO in cardiac I/R injury. Hypothesis: Administration of EPO at different time points provides varying efficacy in reducing arrhythmias, LV and cardiac mitochondrial dysfunction after cardiac I/R injury. Methods: Male Wistar rats were divided into sham-operated and cardiac I/R group. In I/R group, rats were subdivided into 4 groups (n=10/group): vehicle, EPO pretreatment (P-EPO), EPO given during ischemia (I-EPO), and EPO given at reperfusion onset (R-EPO). EPO was intravenously given to the rats (5000 unit/kg). Rats underwent 30-min LAD ligation followed by 120-min reperfusion. Arrhythmia scores and LV function were recorded throughout the protocol. Then, rats were sacrificed to determine infarct size and mitochondrial function. Results: Cardiac I/R injury induced arrhythmias, LV and mitochondrial dysfunction (Fig . Administration of EPO before or during ischemia, but not at the onset of reperfusion, significantly attenuated LV dysfunction and infarct size. However, EPO did not reduce arrhythmia scores. Although EPO given at all time points reduced mitochondrial reactive oxygen species, EPO given at reperfusion failed to prevent mitochondrial swelling (Fig) . Conclusions: Acute EPO treatment before or during ischemia, but not at the onset of reperfusion, exerted cardioprotection against I/R injury.

scholarly journals Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Anthony R. Anzell ◽  
Garrett M. Fogo ◽  
Zoya Gurm ◽  
Sarita Raghunayakula ◽  
Joseph M. Wider ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Conditional Knockout ◽  
Mitochondrial Morphology ◽  
Primary Neurons ◽  
Mitochondrial Fragmentation

AbstractMitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

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