The Role of Superoxide and Nitric Oxide in the Development of Myocardial Injury in Rat Myocarditis.

The mechanism of myocardial injury in myocarditis is still unclear. Recently, nitric oxide (NO), massively produced in the inflammation, has been suggested to be harmful for tissue at excess amount as well as superoxide. However, it is still unclear the relationship between production of NO with superoxide and myocardial damage in myocarditis. In this study, we investigated whether NO and/or superoxide play an important role in the pathogenesis of myocardial injury in myocarditis.The heart tissue specimens were taken from Lewis rats with experimentally induced myocarditis. Immunohistochemical staining was performed using polyclonal antibody for inducible NO synthase by avidin-biotin peroxidase complex method in paraffin sections of the tissue. Histochemical study for ultrastructural H2O2-producing site in the heart tissue was carried out by Brigg’ s method using CeCl3; briefly, the heart tissues were incubated in 0.1M Tris-malate buffer with ImM CeCl3 and 10mM aminotriazole. Then tissues were fixed in 2% glutaraldehyde, postfixed with 1% OsO4 and embedded in resin for electron microscopy.

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Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa154 ◽

2020 ◽

Author(s):

Kang Zhou ◽

Yan Xu ◽

Qiong Wang ◽

Lini Dong

Keyword(s):

Cell Viability ◽

Cell Apoptosis ◽

Myocardial Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Damage ◽

Protective Role ◽

Human Cardiomyocytes ◽

Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

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Abstract 060: CCN1/a 6 β 1 Mediates Myocardial Injuries Induced by Work Overload or by Doxorubicin in Mice

Circulation Research ◽

10.1161/res.113.suppl_1.a060 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Pei-Ling I Hsu ◽

Fan-E Mo

Keyword(s):

Myocardial Injury ◽

Fas Ligand ◽

Cardiac Injury ◽

Pressure Overload ◽

Myocardial Damage ◽

Matricellular Protein ◽

Work Overload ◽

Myocardial Injuries ◽

Injury Models

Introduction: Matricellular protein CCN1 is expressed in myocardial infarction, pressure overload, and ischemia in mice, and in patients with a failing heart. Despite its well-documented angiogenic activities, CCN1 promotes fibroblast apoptosis in some contexts. The role of CCN1 in an injured heart was not clear. We assessed the hypothesis that CCN1 plays a detrimental role and mediates cardiac injury through its proapoptotic activities. Methods and Results: To test the role of CCN1 in cardiac injury, we employed two different myocardial injury models in mice, including a work-overload-induced injury created by isoproterenol treatment (ISO; 100 mg/kg/day; s.c. for 5 days; n= 6 for each group) and an injury induced by the cardiotoxicity of doxorubicin (DOX, single dose of 15 mg/kg; i.p. sacrificed after 14 days). Ccn1 expression was induced in the damaged myocardium in both injury models. A line of knock-in mice carrying an apoptosis-defective Ccn1 mutant allele, Ccn1-dm , which has disrupted integrin α 6 β 1 binding sites, were tested in the ISO- or DOX -induced cardiac injury. Myocardial damage was seen in tissues from wile-type (WT) hearts after receiving ISO. Ccn1 dm/dm (DM) mice possessed remarkable resistance against ISO or DOX treatments and exhibited no tissue damage or fibrosis compared to WT mice after H&E or Masson’s trichrome stainings. DM mice were resistant to both ISO- and DOX-induced cardiac cell apoptosis, indicating that CCN1 is critically mediating cardiomyocyte apoptotic death in cardiac injury. Moreover, we found that death factor Fas ligand (FasL) and its receptor Fas were upregulated in WT mice receiving ISO or DOX treatments by immunohistochemical staining, compared with the PBS-control. 8-OHdG-positive, a marker for oxidative stress, cardiomyocytes were increased by ISO or DOX treatments as well. In contrast, the expression of Fas/FasL, and the 8-OHdG-positive cardiomyocytes in the myocardium of DM mice were not changed by ISO or DOX. Conclusions: We identify CCN1 as a novel pathophysiological regulator of cardiomyocyte apoptosis in cardiac injury. Blocking apoptotic function of CCN1 effectively prevents myocardial injury in mice. CCN1 and its receptor α 6 β 1 represent promising future therapeutic targets in cardiac injury.

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Role of endothelial nitric oxide in control of peripheral vascular conductance during muscle metaboreflex activation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00515.2016 ◽

2017 ◽

Vol 313 (1) ◽

pp. R29-R34

Author(s):

Danielle Senador ◽

Jasdeep Kaur ◽

Alberto Alvarez ◽

Hanna W. Hanna ◽

Abhinav C. Krishnan ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiac Output ◽

Arterial Pressure ◽

Vascular Conductance ◽

Muscle Metaboreflex ◽

Peripheral Vasodilation ◽

Dependent Flow ◽

Flow Mediated Vasodilation ◽

The Relationship

The muscle metaboreflex is a powerful pressor reflex induced by the activation of chemically sensitive muscle afferents as a result of metabolite accumulation. During submaximal dynamic exercise, the rise in arterial pressure is primarily due to increases in cardiac output, since there is little systemic vasoconstriction. Indeed, in normal animals, we have often shown a small, but significant, peripheral vasodilation during metaboreflex activation, which is mediated, at least in part, by release of epinephrine and activation of vascular β2-receptors. We tested whether this vasodilation is in part due to increased release of nitric oxide caused by the rise in cardiac output eliciting endothelium-dependent flow-mediated vasodilation. The muscle metaboreflex was activated via graded reductions in hindlimb blood flow during mild exercise with and without nitric oxide synthesis blockade [ NG-nitro-l-arginine methyl ester (l-NAME); 5 mg/kg]. We assessed the role of increased cardiac output in mediating peripheral vasodilation via the slope of the relationship between the rise in nonischemic vascular conductance (conductance of all vascular beds excluding hindlimbs) vs. the rise in cardiac output. l-NAME increased mean arterial pressure at rest and during exercise. The metaboreflex-induced increases in mean arterial pressure were unaltered by l-NAME, whereas the increases in cardiac output and nonischemic vascular conductance were attenuated. However, the slope of the relationship between nonischemic vascular conductance and cardiac output was not affected by l-NAME, indicating that the rise in cardiac output did not elicit vasodilation via increased release of nitric oxide. Thus, although nitric oxide is intrinsic to the vascular tonus, endothelial-dependent flow-mediated vasodilation plays little role in the small peripheral vasodilation observed during muscle metaboreflex activation.

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Role of pH in a nitric oxide-dependent increase in cytosolic Cl− in retinal amacrine cells

Journal of Neurophysiology ◽

10.1152/jn.00057.2011 ◽

2011 ◽

Vol 106 (2) ◽

pp. 641-651 ◽

Cited By ~ 3

Author(s):

Emily McMains ◽

Evanna Gleason

Keyword(s):

Nitric Oxide ◽

Cell Voltage ◽

Amacrine Cells ◽

Excitatory Synapses ◽

Cytosolic Ph ◽

Ph Imaging ◽

Gabaergic Synapses ◽

The Relationship ◽

Cytosolic Acidification

Nitric oxide (NO) synthase-expressing neurons are found throughout the vertebrate retina. Previous work by our laboratory has shown that NO can transiently convert inhibitory GABAergic synapses onto cultured retinal amacrine cells into excitatory synapses by releasing Cl− from an internal store in the postsynaptic cell. The mechanism underlying this Cl− release is currently unknown. Because transport of Cl− across internal membranes can be coupled to proton flux, we asked whether protons could be involved in the NO-dependent release of internal Cl−. Using pH imaging and whole cell voltage-clamp recording, we addressed the relationship between cytosolic pH and cytosolic Cl− in cultured retinal amacrine cells. We found that NO reliably produces a transient decrease in cytosolic pH. A physiological link between cytosolic pH and cytosolic Cl− was established by demonstrating that shifting cytosolic pH in the absence of NO altered cytosolic Cl− concentrations. Strong buffering of cytosolic pH limited the ability of NO to increase cytosolic Cl−, suggesting that cytosolic acidification is involved in generating the NO-dependent elevation in cytosolic Cl−. Furthermore, disruption of internal proton gradients also reduced the effects of NO on cytosolic Cl−. Taken together, these results suggest a cytosolic environment where proton and Cl− fluxes are coupled in a dynamic and physiologically meaningful way.

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Role of the l-arginine/nitric oxide pathway in ischaemic/reoxygenation injury of the human myocardium

Clinical Science ◽

10.1042/cs0990497 ◽

2000 ◽

Vol 99 (6) ◽

pp. 497-504 ◽

Cited By ~ 4

Author(s):

Jin-Gang ZHANG ◽

Manuel GALIÑANES

Keyword(s):

Nitric Oxide ◽

Bypass Graft ◽

Coronary Bypass ◽

Myocardial Damage ◽

Human Myocardium ◽

Right Atrial ◽

No Donor ◽

Reoxygenation Injury ◽

Synthase Inhibitor

The role of the L-arginine/nitric oxide (NO) pathway in myocardial ischaemic/reperfusion injury remains controversial in experimental animal models. The aim of the present studies was to investigate the role of this pathway in the human myocardium. Myocardial specimens from right atrial appendages of patients undergoing elective coronary bypass graft surgery were incubated in crystalloid buffer at 37 °C and subjected to 120 min of simulated ischaemia followed by 120 min of reoxygenation. Tested drugs were added 15 min before ischaemia, and maintained during ischaemia and throughout reoxygenation. Ischaemia resulted in severe myocardial damage, as assessed by the leakage of lactate dehydrogenase (LDH) into the incubation medium and by the capacity of the tissue to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan product. L-Arginine (10 mM), a precursor of NO, significantly decreased LDH leakage (from 9.0±0.6 to 5.3±0.3 units/g wet wt; P < 0.05), but had no effect on MTT reduction or oxygen consumption. D-Arginine (10 mM), NG-nitro-L-arginine methyl ester (L-NAME; 0.5 mM), an NO synthase inhibitor, and S-nitroso-N-acetylpenicillamine (at 1, 100, 500 and 1000 µM), an NO donor, had no significant effects on the measured indices, and L-NAME did not reverse the protection afforded by L-arginine against LDH leakage. In addition, the formation of nitrotyrosine was not influenced by ischaemia/reoxygenation alone or by the agents investigated. In conclusion, these data suggest that L-arginine affords modest protection against ischaemic/reoxygenation injury of the human myocardium, an action that is NO-independent, and that NO metabolism does not play a significant role in this model.

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Overexpression of lncRNA TUG1 Alleviates NLRP3 Inflammasome-Mediated Cardiomyocyte Pyroptosis Through Targeting the miR-186-5p/XIAP Axis in Coronary Microembolization-Induced Myocardial Damage

Frontiers in Immunology ◽

10.3389/fimmu.2021.637598 ◽

2021 ◽

Vol 12 ◽

Author(s):

You Zhou ◽

Tao Li ◽

Zhiqing Chen ◽

Junwen Huang ◽

Zhenbai Qin ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Myocardial Injury ◽

Culture Supernatant ◽

Myocardial Damage ◽

Luciferase Reporter ◽

Cell Culture Supernatant ◽

Coronary Microembolization ◽

Lncrna Tug1

Coronary microembolization (CME) is a complicated problem that commonly arises in the context of coronary angioplasty. The lncRNA taurine-up regulated gene 1 (TUG1), significantly contributes to cardiovascular diseases; however, its contribution to CME-induced myocardial damage remains elusive. Herein, we establish the rat CME model and investigate the role of TUG1 in CME. The cell viability was evaluated via CCK-8 assay. Serum and cell culture supernatant samples were evaluated via ELISA. The dual luciferase reporter (DLR) assay, RIP, and RNA-pull down were conducted to validate the associations between TUG1 and miR-186-5p as well as miR-186-5p and XIAP. The expression of TUG1, miR-186-5p, and XIAP mRNA were determined by RT-qPCR, and proteins were evaluated via immuneblotting. As a result, TUG1 and XIAP were significantly down-regulated, and the miR-186-5p level was found to be remarkably up-regulated in CME myocardial tissues. Overexpression of TUG1 alleviated CME-induced myocardial injury and pyroptosis, whereas TUG1 knockdown showed the opposite effects. The DLR assay, RIP, and RNA-pull down results reveal that TUG1 directly targets miR-186-5p and miR-186-5p directly targets XIAP. In vitro rescue experiments show that TUG1 overexpression alleviates LPS-caused cardiomyocyte injury and pyroptosis via sponging miR-186-5p and regulating XIAP, and depression of miR-186-5p reduces LPS-induced cardiomyocyte injury and pyroptosis by targeting XIAP. Concludingly, the overexpression of TUG1 alleviates NLRP3 inflammasome-mediated cardiomyocyte pyroptosis through targeting the miR-186-5p/XIAP axis in CME-induced myocardial injury.

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Metabolic aspects of the relationship of asthma and obesity

Obesity and metabolism ◽

10.14341/omet9578 ◽

2019 ◽

Vol 15 (4) ◽

pp. 9-14 ◽

Cited By ~ 3

Author(s):

Oxana Y. Kytikova ◽

Marina V. Antonyuk ◽

Tatyana A. Gvozdenko ◽

Tatyana Р. Novgorodtseva

Keyword(s):

Nitric Oxide ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Common Mechanism ◽

The Metabolic Syndrome ◽

Duration Of Hospitalization ◽

Mechanisms Of Formation ◽

Relationship Of ◽

The Relationship

Asthma and obesity are serious medical and social world problems, and their combined course is characterized by a decrease in the quality of life, an increase in the frequency and duration of hospitalization. The present review summarizes the current views on the mechanisms of formation of asthma phenotype combined with obesity, role of leptin and adiponectin imbalance in the development of systemic inflammation in obesity in the pathophysiology of asthma, its interrelations with metabolic syndrome. We present data that shows that syndrome is closely related not only to the debut of asthma, but also to a decrease in its control. Along with obesity, the role of other components of metabolic syndrome, in particular insulin resistance, as a predictor of asthma development is considered. Insulin resistance may be the most likely factor in the relationship between asthma and obesity, independent of other components of the metabolic syndrome. Insulin resistance associated with obesity can lead to disruption of nitric oxide synthesis. We reveal common mechanism of metabolic disorders of nitric oxide and arginine in metabolic syndrome and asthma and show that insulin resistance treatment can be therapeutically useful in patients with asthma in combination with obesity.

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Pathogenetic significance of C774T single nucleotide polymorphism of the endothelial NO synthase gene in the development of metabolic syndrome

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20166204447 ◽

2016 ◽

Vol 62 (4) ◽

pp. 447-452 ◽

Cited By ~ 1

Author(s):

N.S. Fattakhov ◽

M.A. Vasilenko ◽

D.A. Skuratovskaia ◽

D.I. Kulikov ◽

E.V. Kirienkova ◽

...

Keyword(s):

Nitric Oxide ◽

Metabolic Syndrome ◽

Single Nucleotide Polymorphism ◽

Serum Levels ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Nos3 Gene ◽

Kaliningrad Region ◽

The Relationship

The relationship between nitric oxide production and metabolic disorders and the role of endothelial nitric oxide synthase (eNOS or NOS3) in metabolic syndrome (MS) remain poorly understood and need deeper investigation. In this context the role of the NOS3 gene in pathogenesis of MS is of special interest. The aim of the study was to investigate association of NOS3 single nucleotide polymorphism C774T with risk of MS in the Slavic population of the Kaliningrad region and the relationship of this polymorphic variant with some parameters of endothelial dysfunction. The study included 128 patients (48 men and 80 women aged from 36 to 52 years) with MS. The control group consisted of 126 healthy volunteers (60 men and 66 women aged from 30 to 40 years). Genotyping was performed by real-time PCR. Serum nitrite levels were determined spectrophotometrically by the Griess method. Serum levels of endothelin-1 and eNOS were evaluated by ELISA. The study has shown association of T allele (OR=2.06; p=0.0004; CI: 1.38-3.08) and CT genotype (OR=1.97; p=0.014; CI: 1.14-3.40 ) C774T polymorphism of the NOS3 gene with risk of MS in the Slavic population of the Kaliningrad region. Allele C (OR=0.48; p=0.0004; CI: 0.32-0.72) and homozygous CC genotype (OR=0.41; p=0.001; CI: 0.24-0,69) C774T polymorphism of the NOS3 gene were associated with reduced risk of the development of MS. Significant differences in serum levels of eNOS and endothelin-1 depended on the CT and TT genotypes of C774T polymorphism of the NOS3 gene in MS.

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