scholarly journals Combination ART-Induced Oxidative/Nitrosative Stress, Neurogenic Inflammation and Cardiac Dysfunction in HIV-1 Transgenic (Tg) Rats: Protection by Mg

2018 ◽  
Vol 19 (8) ◽  
pp. 2409 ◽  
Author(s):  
I. Tong Mak ◽  
Joanna J. Chmielinska ◽  
Christopher F. Spurney ◽  
William B. Weglicki ◽  
Jay H. Kramer
Keyword(s):  
Oxidative Stress ◽  
Substance P ◽  
Cardiac Dysfunction ◽  
Neurogenic Inflammation ◽  
Nitrosative Stress ◽  
Contractile Function ◽  
Stress Injury ◽  
Chronic Effects ◽  
Neutrophil Superoxide ◽  
Hiv 1

Chronic effects of a combination antiretroviral therapy (cART = tenofovir/emtricitatine + atazanavir/ritonavir) on systemic and cardiac oxidative stress/injury in HIV-1 transgenic (Tg) rats and protection by Mg-supplementation were assessed. cART (low doses) elicited no significant effects in normal rats, but induced time-dependent oxidative/nitrosative stresses: 2.64-fold increased plasma 8-isoprostane, 2.0-fold higher RBC oxidized glutathione (GSSG), 3.2-fold increased plasma 3-nitrotyrosine (NT), and 3-fold elevated basal neutrophil superoxide activity in Tg rats. Increased NT staining occurred within cART-treated HIV-Tg hearts, and significant decreases in cardiac systolic and diastolic contractile function occurred at 12 and 18 weeks. HIV-1 expression alone caused modest levels of oxidative stress and cardiac dysfunction. Significantly, cART caused up to 24% decreases in circulating Mg in HIV-1-Tg rats, associated with elevated renal NT staining, increased creatinine and urea levels, and elevated plasma substance P levels. Strikingly, Mg-supplementation (6-fold) suppressed all oxidative/nitrosative stress indices in the blood, heart and kidney and substantially attenuated contractile dysfunction (>75%) of cART-treated Tg rats. In conclusion, cART caused significant renal and cardiac oxidative/nitrosative stress/injury in Tg-rats, leading to renal Mg wasting and hypomagnesemia, triggering substance P-dependent neurogenic inflammation and cardiac dysfunction. These events were effectively attenuated by Mg-supplementation likely due to its substance P-suppressing and Mg’s intrinsic anti-peroxidative/anti-calcium properties.

scholarly journals Experimental Hypomagnesemia Induces Neurogenic Inflammation and Cardiac Dysfunction

Hearts ◽  
2020 ◽  
Vol 1 (2) ◽  
pp. 99-116
Author(s):  
Jay H. Kramer ◽  
I. Tong Mak ◽  
Joanna J. Chmielinska ◽  
Christopher F. Spurney ◽  
Terry M. Phillips ◽  
...  
Keyword(s):  
Substance P ◽  
Cardiac Dysfunction ◽  
Neurogenic Inflammation ◽  
Nitrosative Stress ◽  
Disease Status ◽  
Neutral Endopeptidase ◽  
Receptor Blockade ◽  
Mg Deficiency ◽  
Substance P Receptor ◽  
Experimental Findings

Hypomagnesemia occurs clinically as a result of restricted dietary intake, Mg-wasting drug therapies, chronic disease status and may be a risk factor in patients with cardiovascular disorders. Dietary restriction of magnesium (Mg deficiency) in animal models produced a pro-inflammatory/pro-oxidant condition, involving hematopoietic, neuronal, cardiovascular, renal and other systems. In Mg-deficient rodents, early elevations in circulating levels of the neuropeptide, substance P (SP) may trigger subsequent deleterious inflammatory/oxidative/nitrosative stress events. Evidence also suggests that activity of neutral endopeptidase (NEP, neprilysin), the major SP-degrading enzyme, may be impaired during later stages of Mg deficiency, and this may sustain the neurogenic inflammatory response. In this article, experimental findings using substance P receptor blockade, NEP inhibition, and N-methyl-D-aspartate (NMDA) receptor blockade demonstrated the connection between hypomagnesemia, neurogenic inflammation, oxidative stress and enhanced cardiac dysfunction. Proof of concept concerning neurogenic inflammation is provided using an isolated perfused rat heart model exposed to acute reductions in perfusate magnesium concentrations.

scholarly journals Substance P Antagonism Prevents Chemotherapy-Induced Cardiotoxicity

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1732
Author(s):  
Ashiq Legi ◽  
Emma Rodriguez ◽  
Thomas K. Eckols ◽  
Cyrus Mistry ◽  
Prema Robinson
Keyword(s):  
Oxidative Stress ◽  
Body Weight ◽  
Substance P ◽  
Group Treatment ◽  
Cardiac Dysfunction ◽  
Annexin V ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Functional Parameters ◽  
Cardiac Apoptosis

Background: Doxorubicin (DOX), used in chemotherapeutic regimens in many cancers, has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. We determined the role of Substance P (SP), a neuropeptide and its high affinity receptor, NK-1R in chemotherapy associated cardiotoxicity in mice. We determined if NK-1R antagonism will prevent DOX-induced cardiotoxicity in vivo. Methods: C57BL/6 mice (6- week old male) were injected intraperitoneally with DOX (5 mg per kilogram of body weight once a week for 5 weeks) with or without treatment with aprepitant (a NK-1R antagonist, Emend, Merck & Co., Kenilworth, NJ, USA). Five different dosages of aprepitant were administered in the drinking water five days before the first injection of DOX and then continued until the end of the experiment. Each of these 5 doses are as follows; Dose 1 = 0.9 µg/mL, Dose 2 = 1.8 µg/mL, Dose 3 = 3.6 µg/mL, Dose 4 = 7.2 µg/mL, Dose 5 = 14.4 µg/mL. Controls consisted of mice injected with PBS (instead of DOX) with or without aprepitant treatment. The experiment was terminated 5 weeks post-DOX administration and various cardiac functional parameters were determined. Following euthanization, we measured heart weight to body weight ratios and the following in the hearts, of mice treated with and without DOX and aprepitant; (a) levels of SP and NK1R, (b) cardiomyocyte diameter (to determine evidence of cardiomyocyte hypertrophy), (c) Annexin V levels (to determine evidence of cardiac apoptosis), and (d) ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) (to determine evidence of oxidative stress). Results: We demonstrated that the levels of SP and NK1R were significantly increased respectively by 2.07 fold and 1.86 fold in the hearts of mice treated with versus without DOX. We determined that DOX-induced cardiac dysfunction was significantly attenuated by treatment with aprepitant. Cardiac functional parameters such as fractional shortening (FS), ejection fraction (EF) and stroke volume (SV) were respectively decreased by 27.6%, 21.02% and 21.20% compared to the vehicle treated group (All, p < 0.05, ANOVA). Importantly, compared to treatment with DOX alone, treatment with lower doses of aprepitant in DOX treated mice significantly reduced the effects of DOX on FS, EF and SV to values not significantly different from sham (vehicle treated) mice (All, p < 0.05, ANOVA). The levels of, apoptosis marker (Annexin V), oxidative stress (ratio of GSH with GSSG) and cardiomyocyte hypertrophy were respectively increased by 47.61%, 91.43% and 47.54% in the hearts of mice treated with versus without DOX. Compared to the DOX alone group, treatment with DOX and Dose 1, 2 and 3 of aprepitant significantly decreased the levels of each of these parameters (All p < 0.05, ANOVA). Conclusions: Our studies indicate that the SP/NK1-R system is a key mediator that induces, DOX-induced, cardiac dysfunction, cardiac apoptosis, cardiac oxidative stress and cardiomyocyte hypertrophy. These studies implicate that NK-1R antagonists may serve as a novel therapeutic tool for prevention of chemotherapy induced cardiotoxicity in cancer.

scholarly journals Oxidative-Nitrosative Stress and Myocardial Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
M. Neri ◽  
I. Riezzo ◽  
C. Pomara ◽  
S. Schiavone ◽  
E. Turillazzi
Keyword(s):  
Oxidative Stress ◽  
Current Literature ◽  
Cardiac Dysfunction ◽  
Nitrosative Stress ◽  
Myocardial Dysfunction ◽  
Critical Role ◽  
Therapeutic Effects ◽  
Oxidative And Nitrosative Stress ◽  
Antioxidant Agents

Background. Myocardial depression in sepsis is common, and it is associated with higher mortality. In recent years, the hypothesis that the myocardial dysfunction during sepsis could be mediated by ischemia related to decreased coronary blood flow waned and a complex mechanism was invoked to explain cardiac dysfunction in sepsis. Oxidative stress unbalance is thought to play a critical role in the pathogenesis of cardiac impairment in septic patients.Aim. In this paper, we review the current literature regarding the pathophysiology of cardiac dysfunction in sepsis, focusing on the possible role of oxidative-nitrosative stress unbalance and mitochondria dysfunction. We discuss these mechanisms within the broad scenario of cardiac involvement in sepsis.Conclusions. Findings from the current literature broaden our understanding of the role of oxidative and nitrosative stress unbalance in the pathophysiology of cardiac dysfunction in sepsis, thus contributing to the establishment of a relationship between these settings and the occurrence of oxidative stress. The complex pathogenesis of septic cardiac failure may explain why, despite the therapeutic strategies, sepsis remains a big clinical challenge for effectively managing the disease to minimize mortality, leading to consideration of the potential therapeutic effects of antioxidant agents.

Abstract 424: Loss of Sirt2 Protects Against Pressure Overload- and Ischemic Reperfusion Injury-induced Cardiac Dysfunction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Teruki Sato ◽  
Xiaoyan Yan ◽  
Hsiang-Chun Chang ◽  
Chen Chunlei ◽  
Jason S Shapiro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Reperfusion Injury ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Cardiac Response ◽  
Neonatal Rat ◽  
Ros Production ◽  
Wild Type ◽  
Stress Injury

Introduction: Sirtuins are NAD+ dependent deacetylases and critical regulators of energy metabolism and response to oxidative stress. Sirtuin2 (SIRT2) is a cytoplasmic member of the sirtuin family, and has been shown to regulate cellular iron homeostasis through deacetylation of nuclear factor erythroid-derived 2-related factor 2 (NRF2). However, whether SIRT2-NRF2 pathway is involved in the development of heart failure remains unknown. Methods and results: To investigate the functional role of SIRT2 in the response to cardiac stress, SIRT2 knockout (KO) mice and their littermate controls were subjected to pressure overload by transverse aortic constriction (TAC). SIRT2 KO had normal appearance and cardiovascular parameters at baseline. However, in response to TAC, Sirt2 -/- mice displayed resistance to the pathological hypertrophic response, whereas wild type (WT) mice developed cardiac hypertrophy and heart failure. In addition, SIRT2 KO mice displayed less cardiac damage after /reperfusion injury. SIRT2 knockdown in neonatal rat cardiomyocytes (NRCM) reduced reactive oxygen species (ROS) production and cell death after H2O2 treatment. Since cellular oxidative stress is one of major contributor of cardiac dysfunction caused by both I/R injury and pressure overload, we examined whether NRF2 is associated with SIRT2-mediated cardiac response to oxidative stress. Levels of NRF2 was upregulated in NRCM with SIRT2 knockdown and treated with H2O2 compared to wild type (WT) cells. Moreover, NRF2 is translocated into the nucleus and its anti-oxidant target proteins are upregulated in NRCM with SIRT2 knockdown. SIRT2 was also found to bind and deacetylate NRF2 directly as determined by co-immunoprecipitation studies. This led to a reduction of its nuclear translocation and transcriptional activity. Finally, knockdown of both SIRT2 and NRF2 diminished the effects of SIRT2 knockdown on ROS production and cellular damage. Conclusion: These results indicate that SIRT2 contributes to pressure overload and I/R injury induced heart impairment in mice, and promotes oxidative stress injury in cardiomyocytes via deacetylating NRF2 and altering its activity.

Substance P acts via the neurokinin receptor 1 to elicit bronchoconstriction, oxidative stress, and upregulated ICAM-1 expression after oil smoke exposure

2008 ◽  
Vol 294 (5) ◽  
pp. L912-L920 ◽  
Author(s):  
Ping-Chia Li ◽  
Wen-Chung Chen ◽  
Li-Ching Chang ◽  
Shao-Chieh Lin
Keyword(s):  
Oxidative Stress ◽  
Substance P ◽  
Vitamin C ◽  
Receptor Antagonist ◽  
Evans Blue ◽  
Neurogenic Inflammation ◽  
Smoke Exposure ◽  
Plasma Extravasation ◽  
Dependent Manner ◽  
India Ink

This study aimed to 1) assess whether substance P (SP) acts via neurokinin (NK)-1 and NK-2 receptors to stimulate neurogenic inflammation (indicated by formation of ICAM-1 expression and oxidative stress) following oil smoke exposure (OSE) in rats; and 2) determine if pretreatment with antioxidants ameliorates the deleterious effects of OSE. Rats were pretreated with NK-1 receptor antagonist CP-96345, NK-2 receptor antagonist SR-48968, vitamin C, or catechins. OSE was for 30–120 min. Rats were killed 0–8 h later. Total lung resistance ( RL), airway smooth muscle activity (ASMA), lung ICAM-1 expression, neurogenic plasma extravasation (via India ink and Evans blue dye), bronchoalveolar lavage fluid SP concentrations, and reactive oxygen species formation [via lucigenin- and luminal-amplified chemiluminescence (CL)] were assessed. Lung histology was performed. SP concentrations increased significantly in nonpretreated rats following OSE in a dose-dependent manner. RL and total ASMA increased over time after OSE. Vitamin C and catechin pretreatments were associated with significantly reduced lucigenin CL 2 and 4 h after OSE. Pretreatment with catechins significantly reduced luminal CL counts 4 and 8 h after OSE. Evans blue levels were significantly reduced following 60 and 120 min of OSE in catechin- and CP-96345-pretreated rats. ICAM-1 protein expression was significantly decreased in all pretreatment groups after OSE. Thickening of the alveolar capillary membrane, focal hemorrhaging, interstitial pneumonitis, and peribronchiolar inflammation were apparent in OSE lungs. These findings suggest that SP acts via the NK-1 receptor to provoke neurogenic inflammation, oxidative stress, and ICAM-1 expression after OSE in rats.

scholarly journals Oxidative Stress during HIV Infection: Mechanisms and Consequences

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Alexander V. Ivanov ◽  
Vladimir T. Valuev-Elliston ◽  
Olga N. Ivanova ◽  
Sergey N. Kochetkov ◽  
Elizaveta S. Starodubova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Defense Mechanisms ◽  
Nitrosative Stress ◽  
Current Data ◽  
Biological Molecules ◽  
Natural Processes ◽  
Stress Markers ◽  
The Status ◽  
Infection Mechanisms ◽  
Hiv 1

It is generally acknowledged that reactive oxygen species (ROS) play crucial roles in a variety of natural processes in cells. If increased to levels which cannot be neutralized by the defense mechanisms, they damage biological molecules, alter their functions, and also act as signaling molecules thus generating a spectrum of pathologies. In this review, we summarize current data on oxidative stress markers associated with human immunodeficiency virus type-1 (HIV-1) infection, analyze mechanisms by which this virus triggers massive ROS production, and describe the status of various defense mechanisms of the infected host cell. In addition, we have scrutinized scarce data on the effect of ROS on HIV-1 replication. Finally, we present current state of knowledge on the redox alterations as crucial factors of HIV-1 pathogenicity, such as neurotoxicity and dementia, exhaustion of CD4+/CD8+T-cells, predisposition to lung infections, and certain side effects of the antiretroviral therapy, and compare them to the pathologies associated with the nitrosative stress.

scholarly journals Downregulation of miR-128 Ameliorates Ang II-Induced Cardiac Remodeling via SIRT1/PIK3R1 Multiple Targets

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Heqin Zhan ◽  
Feng Huang ◽  
Qian Niu ◽  
Mingli Jiao ◽  
Xumeng Han ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Cultured Cells ◽  
Ang Ii ◽  
Stress Injury ◽  
And Oxidative Stress

Recent studies reported that miR-128 was differentially expressed in cardiomyocytes in response to pathologic stress. However, its function and mechanism remain to be fully elucidated. The aim of the present study was to investigate the role of miR-128 in chronic angiotensin II (Ang II) infusion-induced cardiac remodeling and its underlying mechanism. The cardiac remodeling and heart failure in vivo were established in C57BL/6 mice by chronic subcutaneous Ang II delivery. Knocking down miR-128 was conducted in the hearts of the mice by intravenous injection of HBAAV2/9-miR-128-GFP sponge (miR-128 inhibitor). In vitro experiments of cardiac hypertrophy, apoptosis, and aberrant autophagy were performed in cultured cells after Ang II treatment or transfection of miR-128 antagomir. Our results showed that chronic Ang II delivery for 28 days induced cardiac dysfunction, hypertrophy, fibrosis, apoptosis, and oxidative stress in the mice, while the miR-128 expression was notably enhanced in the left ventricle. Silencing miR-128 in the hearts of mice ameliorated Ang II-induced cardiac dysfunction, hypertrophy, fibrosis apoptosis, and oxidative stress injury. Moreover, Ang II induced excessive autophagy in the mouse hearts, which was suppressed by miR-128 knockdown. In cultured cells, Ang II treatment induced a marked elevation in the miR-128 expression. Downregulation of miR-128 in the cells by transfection with miR-128 antagomir attenuated Ang II-induced apoptosis and oxidative injury probably via directly targeting on the SIRT1/p53 pathway. Intriguingly, we found that miR-128 inhibition activated PIK3R1/Akt/mTOR pathway and thereby significantly damped Ang II-stimulated pathological autophagy in cardiomyocytes, which consequently mitigated cell oxidative stress and apoptosis. In conclusion, downregulation of miR-128 ameliorates Ang II-provoked cardiac oxidative stress, hypertrophy, fibrosis, apoptosis, and dysfunction in mice, likely through targeting on PIK3R1/Akt/mTORC1 and/or SIRT1/p53 pathways. These results indicate that miR-128 inhibition might be a potent therapeutic strategy for maladaptive cardiac remodeling and heart failure.

Abstract 188: Contractile Function and Myofilament Proteins of the Naked Mole-rat Heart Show Resistance to Oxidative Stress

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kelly M Grimes ◽  
David Barefield ◽  
David A Kramer ◽  
Sakthivel Sadayappan ◽  
Rochelle Buffenstein
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Contractile Function ◽  
Fold Increase ◽  
Functional Changes ◽  
Cardiac Reserve ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Fractional Shortening

The naked mole-rat (NMR) is the longest-lived rodent, with a maximum lifespan of >31 years. Unlike every other mammal studied to date, this species withstands cardiovascular structural and functional changes for at least 75% of its lifespan. Due to the intersection of oxidative stress, aging, and cardiovascular disease, we questioned if NMRs were more resistant to oxidative stress-induced cardiac dysfunction compared to short-lived mice. Echocardiography showed that 7 days after a 20 mg/kg dose of doxorubicin (DOX), mice had a 25% decline in fractional shortening (36 ± 1% to 27 ± 2%). In contrast, the fractional shortening of NMRs was unchanged with DOX treatment (27 ± 1%). Previously we observed that while basal cardiac function is low, NMRs have a robust cardiac reserve, displaying a 1.7 fold increase in fractional shortening under exercise-like conditions. DOX-treated NMRs had a significant reduction in their dobutamine response, signifying a diminished cardiac reserve. Intriguingly, we found no changes in phosphorylation or expression of myofilament proteins in the NMR heart with DOX treatment. Mice on the other hand, increased the phosphorylation of cardiac myosin binding protein-C and switched expression from predominantly α-myosin heavy chain to the β-isoform. Electron microscopy showed that DOX caused marked mitochondrial swelling and loss of cristae as well as massive cardiac myofibrillar disarray in mice. Conversely, DOX-treated NMRs had only slight alterations to myofilament structure. NMRs additionally had twofold higher levels of glutathione in their hearts, indicating a high antioxidant capacity. These findings reveal that long-lived NMRs are less susceptible to oxidative stress-induced cardiac dysfunction than mice. The NMR’s low basal cardiac function, unique regulation of myofilament proteins, and high glutathione levels may all be integral in the species’ ability to withstand oxidative damage and preserve cardiac function well into its third decade of life.

Hydrogen peroxide causes cardiac dysfunction independent from its effects on matrix metalloproteinase-2 activationThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 341-348 ◽  
Author(s):  
Hernando León ◽  
Norma Bautista-López ◽  
Jolanta Sawicka ◽  
Richard Schulz
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Gelatin Zymography ◽  
High Energy ◽  
Matrix Metalloproteinase 2 ◽  
High Energy Phosphates ◽  
Stress Injury ◽  
Rat Hearts

Hydrogen peroxide (H2O2) causes cardiac dysfunction through multiple mechanisms. As oxidative stress can activate matrix metalloproteinases (MMPs) and, in particular, MMP-2 activity is associated with oxidative stress injury in the heart, we hypothesized that MMP-2 activation by H2O2 in isolated rat hearts contributes to cardiac dysfunction in this model. Isolated working rat hearts were perfused at 37 °C with a recirculating Krebs–Henseleit buffer ± 5 mmol/L pyruvate, known to protect hearts from oxidative stress. H2O2 (300 µmol/L) was added as a single bolus after 20 min of equilibration, and cardiac function was monitored for 60 min. MMPs activities in both the heart and perfusate samples were assessed by gelatin zymography. Tissue high energy phosphates were analysed by HPLC. The actions of 2 MMP inhibitors, doxycycline (75 µmol/L) or Ro 31-9790 (3 µmol/L), were also assessed. H2O2 at 300 µmol/L produced a rapid decline in cardiac mechanical function, which was maximal at 5 min. A peak in perfusate MMP-2 activity was also observed at 5 min. The deleterious effect of H2O2 on cardiac function was abolished by pyruvate but not by the MMPs inhibitors. This study suggests that in intact hearts, H2O2 induces contractile dysfunction independent of MMPs activation.

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