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.

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.

Hypertrophied myocardium is vulnerable to ischemia/reperfusion injury and refractory to rapamycin-induced protection due to increased oxidative/nitrative stress

2018 ◽  
Vol 132 (1) ◽  
pp. 93-110 ◽  
Author(s):  
Lei-Lei Ma ◽  
Yang Li ◽  
Pei-Pei Yin ◽  
Fei-Juan Kong ◽  
Jun-Jie Guo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Coronary Artery Ligation ◽  
Nitrative Stress ◽  
Cardioprotective Effects

Left ventricular hypertrophy (LVH) is causally related to increased morbidity and mortality following acute myocardial infarction (AMI) via still unknown mechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in normal animals, whether rapamycin-elicited cardioprotection is altered in the presence of LVH has yet to be determined. Pressure overload induced cardiac hypertrophied mice and sham-operated controls were exposed to AMI by coronary artery ligation, and treated with vehicle or rapamycin 10 min before reperfusion. Rapamycin produced marked cardioprotection in normal control mice, whereas pressure overload induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited cardioprotection evidenced by augmented infarct size, aggravated cardiomyocyte apoptosis, and worsening cardiac function. Rapamycin alleviated MI/R injury via ERK-dependent antioxidative pathways in normal mice, whereas cardiac hypertrophied mice manifested markedly exacerbated oxidative/nitrative stress after MI/R evidenced by the increased iNOS/gp91phox expression, superoxide production, total NO metabolites, and nitrotyrosine content. Moreover, scavenging superoxide or peroxynitrite by selective gp91phox assembly inhibitor gp91ds-tat or ONOO− scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarction, hindered cardiomyocyte apoptosis, and improved cardiac function in aortic-banded mice. However, no additional cardioprotective effects were achieved when we combined rapamycin and gp91ds-tat or EUK134 in ischemic/reperfused hearts with or without LVH. These results suggest that cardiac hypertrophy attenuated rapamycin-induced cardioprotection by increasing oxidative/nitrative stress and scavenging superoxide/peroxynitrite protects the hypertrophied heart from MI/R.

PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated IκBα degradation

2001 ◽  
Vol 281 (6) ◽  
pp. H2612-H2618 ◽  
Author(s):  
Jialin Bao ◽  
Kaori Sato ◽  
Min Li ◽  
Youhe Gao ◽  
Ruhul Abid ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Adhesion Molecule ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Myeloperoxidase Activity ◽  
Intramyocardial Injection ◽  
Iκbα Degradation

PR-39 inhibits proteasome-mediated IκBα degradation and might protect against ischemia-reperfusion injury. We studied PR-39, its truncated form PR-11, and a mutant PR-11AAA, which lacks the ability to prevent IκBα degradation, in a rat heart ischemia-reperfusion model. After 30 min of ischemia and 24 h of reperfusion, cardiac function, infarct size, neutrophil infiltration, and myeloperoxidase activity were measured. Intramyocardial injection of 10 nmol/kg PR-39 or PR-11 at the time of reperfusion reduced infarct size by 65% and 57%, respectively, which improved blood pressure, left ventricular systolic pressure, and relaxation and contractility (±dP/d t) compared with vehicle controls 24 h later. Neutrophil infiltration, myeloperoxidase activity, and the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 and PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the rat in vivo. This effect is mediated by inhibition of IκBα degradation and subsequent inhibition of nuclear factor-κB-dependent adhesion molecules. The active sequence is located in the first 11 amino acids, suggesting a potential for oligopeptide therapy as an adjunct to revascularization.

Abstract P339: The Mechanistic Relationship Between GRK2 and eNOS During Cardiac Ischemia/Reperfusion Injury

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Zheng M Huang ◽  
Erhe Gao ◽  
Xiying Shang ◽  
Xufan Tian ◽  
Gang Qiu ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Cardiac Tissue ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Artery Ligation ◽  
Protein Activity ◽  
Artery Ligation ◽  
Cardiac Phenotype

Background: Previous studies have shown that both cardiac-specific GRK2 transgenic (TG) (αMHC-GRK2) mice and eNOS knockout (KO) mice have larger infarcts after I/R compared to control mice. In contrast, cardiac-targeted eNOS TG mice and cardiac specific GRK2 KO mice show cardioprotection after I/R, suggesting a dynamic interaction between the two proteins. Mechanistically, GRK2 can be inhibited by cellular NO through S-nitrosylation with Cys340 being the major site; meanwhile GRK2 has been shown to directly bind to and inhibit Akt, which is a strong activator of eNOS. Aim: to investigate the potential novel interaction between GRK2 and eNOS, and the consequent functional impact on the protein activity and cardiac phenotype after I/R injury. Methods: αMHC-GRK2 mice were crossed with either eNOS TG or eNOS KO mice. All mice were subjected to sham or 30min myocardial ischemia via coronary artery ligation followed by 24hrs of reperfusion. Infarct size, cardiac function, and tissue apoptosis were examined. Co-IP was used to test the interaction between GRK2 and eNOS, and phosphorylation of eNOS was studied in neonatal myocytes. Results: 1).αMHC-GRK2/eNOS TG hybrid mice showed a significantly reduced infarct size after I/R compared to αMHC-GRK2 mice, accompanied by improved cardiac function measured by echocardiography and hemodynamics, and significantly less apoptosis tested by TUNEL assay, implying a rescue effect by eNOS. 2). αMHC-GRK2/eNOS KO mice exhibited a bigger infarct size compared to either αMHC-GRK2 mice or eNOS KO mice. 3). CO-IP confirmed the interaction between GRK2 and eNOS in cardiac tissue, which was increased upon β-AR agonist treatment. 4). In neonatal ventricular myocytes, GRK2 overexpression significantly decreased eNOS phosphorylation at Ser1177 after exposure to H2O2, while GRK2 knockdown by siRNA led to slight increase in pSer1177. Conclusions: eNOS interacts with and may be a downstream target of GRK2 in the heart. Decreased activation of eNOS may mediate the deleterious effect of GRK2 overexpression during cardiac I/R injury.

Rosuvastatin reduces experimental left ventricular infarct size after ischemia-reperfusion injury but not total coronary occlusion

2005 ◽  
Vol 288 (4) ◽  
pp. H1802-H1809 ◽  
Author(s):  
Ellen O. Weinberg ◽  
Marielle Scherrer-Crosbie ◽  
Michael H. Picard ◽  
Boris A. Nasseri ◽  
Catherine MacGillivray ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Protection ◽  
Coronary Occlusion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Saline Group ◽  
Left Ventricular ◽  
Deficient Mice

This study compared the effects of rosuvastatin on left ventricular infarct size in mice after permanent coronary occlusion vs. 60 min of ischemia followed by 24 h of reperfusion. Statins can inhibit neutrophil adhesion, increase nitric oxide synthase (NOS) expression, and mobilize progenitor stem cells after ischemic injury. Mice received blinded and randomized administration of rosuvastatin (20 mg·kg−1·day−1) or saline from 2 days before surgery until death. After 60 min of ischemia with reperfusion, infarct size was reduced by 18% ( P = 0.03) in mice randomized to receive rosuvastatin ( n = 18) vs. saline ( n = 22) but was similar after permanent occlusion in rosuvastatin ( n = 17) and saline ( n = 20) groups ( P = not significant). Myocardial infarct size after permanent left anterior descending coronary artery occlusion ( n = 6) tended to be greater in NOS3-deficient mice than in the wild-type saline group (33 ± 4 vs. 23 ± 2%, P = 0.08). Infarct size in NOS3-deficient mice was not modified by treatment with rosuvastatin (34 ± 5%, n = 6, P = not significant vs. NOS3-deficient saline group). After 60 min of ischemia-reperfusion, neutrophil infiltration was similar in rosuvastatin and saline groups as was the percentage of CD34+, Sca-1+, and c-Kit+ cells. Left ventricular NOS3 mRNA and protein levels were unchanged by rosuvastatin. Rosuvastatin reduces infarct size after 60 min of ischemia-reperfusion but not after permanent coronary occlusion, suggesting a potential anti-inflammatory effect. Although we were unable to demonstrate that the myocardial protection was due to an effect on neutrophil infiltration, stem cell mobilization, or induction of NOS3, these data suggest that rosuvastatin may be particularly beneficial in myocardial protection after ischemia-reperfusion injury.

Abstract P48: Preconditioning with Periodic Acceleration Significantly Decreases Infarct Size and Arrhythmias after Left Ventricular Ischemia Reperfusion Injury in Rats

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Arkady Uryash ◽  
Heng Wu ◽  
Jaqueline Arias ◽  
Jorge Bassuk ◽  
Paul Kurlansky ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
At Risk ◽  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Male Rats ◽  
Whole Body ◽  
Coronary Artery Ligation ◽  
Periodic Acceleration

BACKGROUND: Whole body periodic acceleration (pGz) is the sinusoidal head-foot motion in the spinal axis. pGz increases pulsatile vascular shear stress to the endothelium, activates endothelial nitric oxide synthase (eNOS) thus promoting increased release of nitric oxide (NO) in pigs, sheep, rats, isolated aorta, and humans. pGz is cardioprotective via NO release 1 hr prior to CPR or during CPR in pigs with induced ventricular fibrillation. The purpose of this study was to ascertain whether acute and chronic pGz preconditioning is cardioprotective in myocardial ischemia reperfusion (I/R) injury in rats as measured by infarction size, and arrhythmias. METHODS: Unsedated, restrained, male rats (310±9 g, n=16) were preconditioned with pGz ( f =6 cps, a =3.4 m/s 2 ). Rats were randomized to: a) pGz 2 hr for 1 day prior to I/R (PRE-pGz 1D) n=4, b) pGz 2 hrs per day for 3 days prior to I/R (PRE-pGz 3D) n=6 and c) Control (C) n=6. Then, they were anesthetized and underwent focal I/R injury by left coronary artery ligation for 30 minutes followed by 120 min of reperfusion. ECG, and aortic pressure were monitored and infarct size calculated as % area at risk. RESULTS: PRE-pGz 3D had an infarct sparring effect of 77% of C. Both 1 and 3 days PRE-pGz significantly attenuated ventricular arrhythmias during reperfusion. Figure below shows % infarct for all groups, † P <0.001 PRE-pGz 3D vs. C, * P <0.001 PRE-pGz 1D vs. C, and representative areas of infarct (INF) and at risk (AAR) in PRE-pGz 3D and C. CONCLUSIONS: pGz preconditioning in rats significantly reduces infarct size and attenuates ventricular arrhythmias. This simple and non-invasive method of cardioprotection for I/R injury warrants human investigations.

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

2012 ◽  
Vol 302 (9) ◽  
pp. H1806-H1817 ◽  
Author(s):  
Jinqiao Qian ◽  
Shukuan Ling ◽  
Alexander C. Castillo ◽  
Bo Long ◽  
Yochai Birnbaum ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxia-induced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation.

Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
G Protein ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

scholarly journals Cardiac surgery in acute myocardial infarction: crystalloid versus blood cardioplegia – an experimental study

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Andreas Boening ◽  
Maximilian Hinke ◽  
Martina Heep ◽  
Kerstin Boengler ◽  
Bernd Niemann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiac Surgery ◽  
Cardiac Function ◽  
Infarct Size ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Cardioplegic Arrest ◽  
Blood Cardioplegia ◽  
Cardioplegia Solution

Abstract Background Because hearts in acute myocardial infarction are often prone to ischemia-reperfusion damage during cardiac surgery, we investigated the influence of intracellular crystalloid cardioplegia solution (CCP) and extracellular blood cardioplegia solution (BCP) on cardiac function, metabolism, and infarct size in a rat heart model of myocardial infarction. Methods Following euthanasia, the hearts of 50 rats were quickly excised, cannulated, and inserted into a blood-perfused isolated heart apparatus. A regional myocardial infarction was created in the infarction group (18 hearts) for 120 min; the control group (32 hearts) was not subjected to infarction. In each group, either Buckberg BCP or Bretschneider CCP was administered for an aortic clamping time of 90 min. Functional parameters were recorded during reperfusion: coronary blood flow, left ventricular developed pressure (LVDP) and contractility (dp/dt max). Infarct size was determined by planimetry. The results were compared between the groups using analysis of variance or parametric tests, as appropriate. Results Cardiac function after acute myocardial infarction, 90 min of cardioplegic arrest, and 90 min of reperfusion was better preserved with Buckberg BCP than with Bretschneider CCP relative to baseline (BL) values (LVDP 54 ± 11% vs. 9 ± 2.9% [p = 0.0062]; dp/dt max. 73 ± 11% vs. 23 ± 2.7% [p = 0.0001]), whereas coronary flow was similarly impaired (BCP 55 ± 15%, CCP 63 ± 17% [p = 0.99]). The infarct in BCP-treated hearts was smaller (25% of myocardium) and limited to the area of coronary artery ligation, whereas in CCP hearts the infarct was larger (48% of myocardium; p = 0.029) and myocardial necrosis was distributed unevenly to the left ventricular wall. Conclusions In a rat model of acute myocardial infarction followed by cardioplegic arrest, application of BCP leads to better myocardial recovery than CCP.

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