scholarly journals Citrulline Improves Early Post-Ischemic Recovery or Rat Hearts In Vitro by Shifting Arginine Metabolism From Polyamine to Nitric Oxide Formation

2018 ◽  
Vol 12 ◽  
pp. 117954681877190 ◽  
Author(s):  
Marc Heidorn ◽  
Tim Frodermann ◽  
Andreas Böning ◽  
Rolf Schreckenberg ◽  
Klaus-Dieter Schlüter
Keyword(s):  
Nitric Oxide ◽  
Functional Recovery ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Adult Rats ◽  
Rat Cardiomyocytes ◽  
No Formation ◽  
Arginase 1 ◽  
Early Functional Recovery

Background: Reperfusion or reopening of occluded vessels is the gold standard to terminate ischemia. However, early functional recovery after reperfusion is often low requiring inotropic intervention. Although catecholamines increase inotropy and chronotropy, they are not the best choice because they increase myocardial oxygen and substrate demand. As nitric oxide (NO) contributes to cardiac function, we tested the hypothesis that addition of citrulline during the onset of reperfusion improves post-ischemic recovery because citrulline can reenter arginine consumption of NO synthases (NOS) but not of arginases. Methods: Hearts from adult rats were used in this study, exposed to 45-minute global ischemia and subsequently reperfused for 180 minutes. Citrulline (100 µM) or arginine (100 µM) was added with reperfusion and remained in the perfusion buffer for 180 minutes. Nω-nitro-l-arginine methyl ester (l-NAME) was used to antagonize NOS activity. Results: Citrulline increased load-free cell shortening of isolated adult rat cardiomyocytes and improved left ventricular developed pressure (LVDP) under normoxic conditions, indicating that citrulline can affect heart function. Ischemia/reperfusion caused a constitutive loss of function during 3 hours of reperfusion, whereas citrulline, but not arginine, improved the functional recovery during reperfusion. This effect was attenuated by co-administration of l-NAME. Although citrulline increased the formation of nitrite, l-NAME attenuated this effect indicating again a positive effect of citrulline on NO formation. Citrulline, but not arginine, increased the expression of arginase-1 (protein and mRNA) but l-NAME attenuated this effect again. Collectively, citrulline improved the post-ischemic recovery in an NO-dependent way. Conclusions: Citrulline, known to block arginase and to support NO formation, improves the early functional recovery of post-ischemic hearts and may be an alternative to catecholamines to improve early post-ischemic recovery.

Abstract 183: Improved Ca-cycling by Dexamethasone Preserves Contractility After Ischemia/Reperfusion in Diabetic Rat Cardiomyocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Christian Schach ◽  
Michael Goetz ◽  
Hendrik Busse ◽  
York Zausig ◽  
Marzena Drymalski ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Cellular Level ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Rat Cardiomyocytes ◽  
Zucker Diabetic Fatty Rats

Glucocorticoid receptor (GR) stimulation is essential for normal heart function and dexamethasone (DEX) treatment has been shown to reduce ischemia reperfusion injury (IRI). Prevalence of diabetes is increasing and myocardial infarction in such patients is more severe and risk of complications is augmented. We tested the hypothesis, that GR stimulation with DEX protects diabetic myocardium from IRI by improving Ca cycling. Cardiomyocytes from type 2 diabetic Zucker diabetic fatty rats were isolated and cultured in DEX (10 μg/mL) vs. vehicle for 24h. [Ca] i and fractional shortening (FS) was measured in electrical field-stimulated cardiomyocytes loaded with Fura-2 AM (10 μM). Compared to control, DEX-treated cells display increased Ca transient amplitude (0.33±0.03 vs. 0.46±0.04, P = 0.01, n=6 animals) and FS (fig.) DEX also significantly increased sarcoplasmic reticulum (SR) Ca content (Caffeine, 10 mM) and reduced SR Ca leak measured as Ca spark frequency (SpF), fluo-4 loaded myocytes, confocal microscopy (fig.). To test, whether DEX reduced IRI, rats were treated with DEX (2 mg/kg i.p.) 24h before measurement (vehicle as control). Left ventricular developed pressure (LVDP) was monitored in Langendorff-perfused-hearts during global ischemia for 30 min and reperfusion. During reperfusion, DEX-treated hearts showed significantly greater LVDP (P < 0.05, 2way ANOVA, fig.). In diabetic rats, glucocorticoid receptor stimulation with DEX leads to a more efficient Ca cycling with reduced SR Ca leakage, which translates to an increased contractility on the cellular level and protection against ischemia reperfusion injury in the whole organ.

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.

GPER mediates estrogen cardioprotection against epinephrine-induced stress

2021 ◽  
Author(s):  
Lu Fu ◽  
Hongyuan Zhang ◽  
Jeremiah Ong’achwa Machuki ◽  
Tingting Zhang ◽  
Lin Han ◽  
...  
Keyword(s):  
Culture Supernatant ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Protective Role ◽  
Left Ventricular ◽  
Internal Diameter ◽  
High Dose ◽  
Adult Rats ◽  
Rat Cardiomyocytes ◽  
Lactate Dehydrogenase Release

Currently, there are no conventional treatments for stress-induced cardiomyopathy (SCM, also known as Takotsubo syndrome), and the existing therapies are not effective. The recently discovered G protein- coupled estrogen receptor (GPER) executes the rapid effects of estrogen (E2). In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose of Epi in adult rats and human-induced pluripotent stem cells–derived cardiomyocytes(hiPSC-CMs). (1) GPER activation with agonist G1/ E2 prevented an increase in left ventricular internal diameter at end-systole, the decrease both in ejection fraction and cardiomyocyte shortening amplitude elicited by Epi. (2) G1/ E2 mitigated heart injury induced by Epi, as revealed by reduced plasma brain natriuretic peptide and lactate dehydrogenase release into culture supernatant. (3) G1/E2 prevented the raised phosphorylation and internalization of β2-adrenergic receptors（β2AR）. (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cyclic adenosine monophosphate concentration in culture supernatant treated with Epi. (5) G1/E2 rescued decreased Ca2+ amplitude and Ca2+ channel current (ICa-L) in rat cardiomyocytes. Notably, the above effects of E2 were blocked by the GPER antagonist, G15. In hiPSC-CM (which expressed GPER, β1AR and β2ARs), knockdown of GPER by siRNA abolished E2 effects on increasing ICa-L and action potential duration in the stress state. In conclusion, GPER played a protective role against SCM. Mechanistically, this effect was mediated by balancing the coupling of β2AR to the Gαs and Gαi signalling pathways.

scholarly journals Inhibition of Myocardial Ischemia/Reperfusion Injury by Exosomes Secreted from Mesenchymal Stem Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Heng Zhang ◽  
Meng Xiang ◽  
Dan Meng ◽  
Ning Sun ◽  
Sifeng Chen
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Left Ventricle ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Area At Risk

Exosomes secreted by mesenchymal stem cells have shown great therapeutic potential in regenerative medicine. In this study, we performed meta-analysis to assess the clinical effectiveness of using exosomes in ischemia/reperfusion injury based on the reports published between January 2000 and September 2015 and indexed in the PUBMED and Web of Science databases. The effect of exosomes on heart function was evaluated according to the following parameters: the area at risk as a percentage of the left ventricle, infarct size as a percentage of the area at risk, infarct size as a percentage of the left ventricle, left ventricular ejection fraction, left ventricular fraction shortening, end-diastolic volume, and end-systolic volume. Our analysis indicated that the currently available evidence confirmed the therapeutic potential of mesenchymal stem cell-secreted exosomes in the improvement of heart function. However, further mechanistic studies, therapeutic safety, and clinical trials are required for optimization and validation of this approach to cardiac regeneration after ischemia/reperfusion injury.

Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion

2005 ◽  
Vol 288 (1) ◽  
pp. H221-H226 ◽  
Author(s):  
Meijing Wang ◽  
Ben M. Tsai ◽  
Ajay Kher ◽  
Lauren B. Baker ◽  
G. Mathenge Wairiuko ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Functional Recovery ◽  
Caspase 3 ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Caspase 1 ◽  
Tnf Α

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-α, IL-1β, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-α, IL-1β, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.

scholarly journals EPR analyzes of nitric oxide (NO) formation in the rats subjected to intestinal ischemia-reperfusion

Shock ◽  
1999 ◽  
Vol 11 (Supplement) ◽  
pp. 57
Author(s):  
Kozlov A. V. ◽  
Sobhian B. ◽  
Bahrami S. ◽  
Nohl H. ◽  
Redl H. L.
Keyword(s):  
Nitric Oxide ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
No Formation ◽  
Intestinal Ischemia Reperfusion

Chronic β-agonist administration affects cardiac function of adult but not old rats, independent of β-adrenoceptor density

2005 ◽  
Vol 289 (1) ◽  
pp. H344-H349 ◽  
Author(s):  
Paul Gregorevic ◽  
James G. Ryall ◽  
David R. Plant ◽  
Martin N. Sillence ◽  
Gordon S. Lynch
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Heart Function ◽  
Relative Increase ◽  
Left Ventricular ◽  
Aged Rats ◽  
Adult Rats ◽  
Age Related ◽  
Heart Mass

Although β-adrenoceptor agonists have clinical merit for attenuating the age-related loss of skeletal muscle mass and strength (sarcopenia), potential cardiac-related side effects may limit their clinical application. The aim of this study was to determine whether chronic β-agonist administration impairs cardiac function in adult or aged rats. Adult (16 mo) and aged (28 mo) Fischer 344 rats were treated with fenoterol (1.4 mg·kg−1·day−1 ip) or vehicle for 4 wk. Heart function was assessed in vitro before analyses of cardiac structure and β-adrenoceptor density. Heart mass increased 17% and 25% in fenoterol-treated adult and aged rats, respectively. The increased heart mass in aged, but not adult, rats was associated with a relative increase in collagen content. Cardiac hypertrophy in adult rats was associated with an increase in left ventricular developed pressure, a marked reduction in cardiac output, and a reduction in coronary flow per unit heart mass. In contrast, negligible differences in ventricular function were observed in fenoterol-treated aged rats. The differential effect on contractile function was not associated with age-related differences in β-adrenoceptor density but, rather, an age-related increase in downregulation after treatment. Our results show that chronic β-agonist treatment impairs cardiac function to a greater extent in adult than in aged rats. These results provide important information regarding the potential effects of chronic β-agonist use on cardiac function and the future development of safe and effective treatments for sarcopenia.

Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction

2011 ◽  
Vol 301 (5) ◽  
pp. H2061-H2072 ◽  
Author(s):  
Takayuki Shimazu ◽  
Hajime Otani ◽  
Kei Yoshioka ◽  
Masanori Fujita ◽  
Toru Okazaki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Functional Recovery ◽  
Capillary Density ◽  
Left Ventricular ◽  
Wild Type ◽  
Beneficial Effects ◽  
End Diastolic Volume ◽  
Lv Remodeling ◽  
And Function

Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS−/−), endothelial NOS-knockout (eNOS−/−), and neuronal NOS-knockout (nNOS−/−) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS−/− mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH4) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH2), BH4, and BH4-to-BH2 ratio in the infarcted but not sham-operated heart. The increase in BH4-to-BH2 ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS−/− mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS−/−, and nNOS−/− but not iNOS−/− mice. Nω-nitro-l-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH4 synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.

scholarly journals Salvia miltiorrhiza treatment during early reperfusion reduced postischemic myocardial injury in the rat

2007 ◽  
Vol 85 (10) ◽  
pp. 1012-1019 ◽  
Author(s):  
Ruqiong Nie ◽  
Rui Xia ◽  
Xingwu Zhong ◽  
Zhengyuan Xia
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Functional Recovery ◽  
Salvia Miltiorrhiza ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Water Soluble ◽  
Causative Role ◽  
Myocardial Ischemia And Reperfusion ◽  
Early Reperfusion

Oxidative stress may play a causative role in myocardial ischemia–reperfusion injury. However, it is a relatively understudied aspect regarding an optimal timing of antioxidant intervention during ischemia–reperfusion. The present study investigates the effect of different treatment regimens of Salvia miltiorrhiza (SM) herb extracts containing phenolic compounds that possess potent antioxidant properties on postischemic myocardial functional recovery in the setting of global myocardial ischemia and reperfusion. Langendorff-perfused rat hearts were subjected to 40 min of global ischemia at 37 °C followed by 60 min of reperfusion, and were randomly assigned into the untreated control and 2 SM-treated groups (n = 7 per group). In treatment 1 (SM1), 3 mg/mL of water soluble extract of SM was given for 10 min before ischemia and continued during ischemia through the aorta at a reduced flow rate of 60 μL/min, but not during reperfusion. In treatment 2 (SM2), SM (3 mg/mL) was given during the first 15 min of reperfusion. During ischemia, hearts in the control and SM2 groups were given physiological saline at 60 μL/min. The SM1 treatment reduced the production of 15-F2t-isoprostane, a specific index of oxidative stress-induced lipid peroxidation, during ischemia (94 ± 20, 43 ± 6, and 95 ± 15 pg/mL in the coronary effluent in control, SM1, and SM2 groups, respectively; p < 0.05, SM1 vs. control or SM2) and postponed the onset of ischemic contracture. However, SM2, but not the SM1 regimen, significantly reduced 15-F2t-isoprostane production during early reperfusion and led to optimal postischemic myocardial functional recovery (left ventricular developed pressure 51 ± 4, 46 ± 4, and 60 ± 6 mmHg in the control, SM1, and SM2 groups, respectively, at 60 min of reperfusion; p < 0.05, SM2 vs. control or SM1) and reduced myocardial infarct size as measured by triphenyltetrazolium chloride staining (26% ± 2%, 22% ± 2%, and 20% ± 2% of the total area in the control, SM1, and SM2 groups, respectively, p < 0.05, SM2 vs. control). It is concluded that S. miltiorrhiza could be beneficial in the treatment of myocardial ischemic injury and the timing of administration seems important.

scholarly journals Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257280
Author(s):  
Yanbo Tang ◽  
Kevin T. Kline ◽  
Xiaoying S. Zhong ◽  
Ying Xiao ◽  
Haifeng Lian ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Neutralizing Antibody ◽  
Brain Derived Neurotrophic Factor ◽  
Left Ventricular ◽  
H9c2 Cells ◽  
Chronic Colitis ◽  
Adult Rats ◽  
Adult Heart

Ulcerative colitis and Crohn’s disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1β as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1β neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1β→miR-155→BDNF signaling axis.

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