scholarly journals Selective TNF-α targeting with infliximab attenuates impaired oxygen metabolism and contractile function induced by an acute exposure to air particulate matter

2015 ◽  
Vol 309 (10) ◽  
pp. H1621-H1628 ◽  
Author(s):  
Timoteo Marchini ◽  
Verónica D'Annunzio ◽  
Mariela L. Paz ◽  
Lourdes Cáceres ◽  
Mariana Garcés ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Saline Solution ◽  
Contractile Function ◽  
Left Ventricular ◽  
Acute Exposure ◽  
Control Group ◽  
Contractile Reserve ◽  
Mice Model ◽  
Cardiovascular Morbidity And Mortality ◽  
Tnf Α

Inflammation plays a central role in the onset and progression of cardiovascular diseases associated with the exposure to air pollution particulate matter (PM). The aim of this work was to analyze the cardioprotective effect of selective TNF-α targeting with a blocking anti-TNF-α antibody (infliximab) in an in vivo mice model of acute exposure to residual oil fly ash (ROFA). Female Swiss mice received an intraperitoneal injection of infliximab (10 mg/kg body wt) or saline solution, and were intranasally instilled with a ROFA suspension (1 mg/kg body wt). Control animals were instilled with saline solution and handled in parallel. After 3 h, heart O2 consumption was assessed by high-resolution respirometry in left ventricle tissue cubes and isolated mitochondria, and ventricular contractile reserve and lusitropic reserve were evaluated according to the Langendorff technique. ROFA instillation induced a significant decrease in tissue O2 consumption and active mitochondrial respiration by 32 and 31%, respectively, compared with the control group. While ventricular contractile state and isovolumic relaxation were not altered in ROFA-exposed mice, impaired contractile reserve and lusitropic reserve were observed in this group. Infliximab pretreatment significantly attenuated the decrease in heart O2 consumption and prevented the decrease in ventricular contractile and lusitropic reserve in ROFA-exposed mice. Moreover, infliximab-pretreated ROFA-exposed mice showed conserved left ventricular developed pressure and cardiac O2 consumption in response to a β-adrenergic stimulus with isoproterenol. These results provides direct evidence linking systemic inflammation and altered cardiac function following an acute exposure to PM and contribute to the understanding of PM-associated cardiovascular morbidity and mortality.

scholarly journals TRPV1 Blocker HCRG21 Suppresses TNF-α Production and Prevents the Development of Edema and Hypersensitivity in Carrageenan-Induced Acute Local Inflammation

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 716
Author(s):  
Oksana Sintsova ◽  
Irina Gladkikh ◽  
Anna Klimovich ◽  
Yulia Palikova ◽  
Viktor Palikov ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Control Group ◽  
Transient Receptor Potential Vanilloid ◽  
Paw Edema ◽  
Mice Model ◽  
Edema Formation ◽  
Sensitivity Experiment ◽  
Tnf Α ◽  
Anti Inflammatory

Currently the TRPV1 (transient receptor potential vanilloid type 1) channel is considered to be one of the main targets for pro-inflammatory mediators including TNF-α. Similarly, the inhibition of TRPV1 activity in the peripheral nervous system affects pro-inflammatory mediator production and enhances analgesia in total. In this study, the analgesic and anti-inflammatory effects of HCRG21, the first peptide blocker of TRPV1, were demonstrated in a mice model of carrageenan-induced paw edema. HCRG21 in doses of 0.1 and 1 mg/kg inhibited edema formation compared to the control, demonstrated complete edema disappearance in 24 h in a dose of 1 mg/kg, and effectively reduced the productionof TNF-α in both doses examined. ELISA analysis of blood taken 24 h after carrageenan administration showed a dramatic cytokine value decrease to 25 pg/mL by HCRG21 versus 100 pg/mL in the negative control group, which was less than the TNF-α level in the intact group (40 pg/mL). The HCRG21 demonstrated potent analgesic effects on the models of mechanical and thermal hyperalgesia in carrageenan-induced paw edema. The HCRG21 relief effect was comparable to that of indomethacin taken orally in a dose of 5 mg/kg, but was superior to this nonsteroidal anti-inflammatory drug (NSAID) in duration (which lasted 24 h) in the mechanical sensitivity experiment. The results confirm the existence of a close relationship between TRPV1 activity and TNF-α production once again, and prove the superior pharmacological potential of TRPV1 blockers and the HCRG21 peptide in particular.

scholarly journals Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3534
Author(s):  
Joseph Aliaga ◽  
Aldo Bonaventura ◽  
Eleonora Mezzaroma ◽  
Yogesh Dhakal ◽  
Adolfo Gabriele Mauro ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Diastolic Function ◽  
Nlrp3 Inflammasome ◽  
Ischemic Cardiomyopathy ◽  
Left Ventricular ◽  
Control Group ◽  
Contractile Reserve ◽  
Standard Diet ◽  
Group 3 ◽  
Group 1

Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction <40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.

P4981The reduction of coronary flow velocity reserve in heart failure with reduced, mid-range or preserved ejection fraction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Daros ◽  
L Cortigiani ◽  
Q Ciampi ◽  
N Gaibazzi ◽  
A Zagatina ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Flow Velocity ◽  
Coronary Flow ◽  
Left Ventricular ◽  
Control Group ◽  
Contractile Reserve ◽  
Coronary Flow Velocity Reserve ◽  
Coronary Flow Velocity ◽  
Asymptomatic Patients

Abstract Background Coronary microvascular disease has been described in heart failure (HF) in presence of angiographically normal epicardial coronary arteries. The prevalence of a reduction of coronary flow velocity reserve (CFVR) in different types of HF and its link with left ventricular contractile reserve (LVCR) is unclear. Aim To assess CFVR and LVCR in HF. Methods In a prospective, observational, multicenter study, we recruited 380 patients (234 male, 61%, age 66±11 years): 143 (38%) with HF and reduced (<40%) ejection fraction (HFrEF); 98 (26%) with HF and mid-range (40–50%) ejection fraction (HFmrEF); 139 (36%) patients with HF and preserved (>50%) ejection fraction (HFpEF). A control group of 52 asymptomatic patients (23 male, 44%, age 61±14 years) referred to testing for screening was also selected (Controls). All patients underwent dipyridamole (0.84 mg/kg) stress echocardiography in 12 accredited laboratories of 3 countries (Argentina, Brazil and Italy). CFVR was calculated as the stress/rest ratio of diastolic peak flow velocity pulsed-Doppler assessment of left anterior descending (LAD) artery flow. We assessed left ventricular contractile reserve (LVCR) based on global LV Force (systolic blood pressure/end-systolic volume). Results Reduced (≤2.0) CFVR was observed in 0/52 controls (0%); 25/139 HFpEF (18%); 28/98 HFmrEF (29%); 78/143 HFrEF (54%, p<0.001 vs all other groups). CFVR was highest in controls (2.80±0.57), lower in HFpEF (2.51±0.57) and HFmrEF (2.26±0.44), lowest in HFrEF (2.04±0.48, p<0.001 vs all other groups). The correlation with LVCR was absent in controls (r=0.098, p=0.491) and HFmrEF (r=0.032, p=0.756), present in HFrEF (r=0.375, p<0.001) and HFpEF (r=0.314, p<0.001). LVCR vs CFVR Conclusions CFVR is frequently abnormal in all types of HF, although more frequently and more profoundly in HFrEF. CFVR mirrors contractile reserve in HFrEF and - less tightly - in HFpEF.

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 Epicardial Fat Thickness as Cardiovascular Risk Factor and Therapeutic Target in Patients with Rheumatoid Arthritis Treated with Biological and Nonbiological Therapies

Arthritis ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Marcos M. Lima-Martínez ◽  
Ediris Campo ◽  
Johanmary Salazar ◽  
Mariela Paoli ◽  
Irama Maldonado ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adipose Tissue ◽  
Therapeutic Target ◽  
Basal Insulin ◽  
Plasma Lipids ◽  
Fasting Blood Glucose ◽  
Left Ventricular ◽  
Control Group ◽  
Cardiovascular Morbidity And Mortality ◽  
Hs Crp

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with high cardiovascular morbidity and mortality. Epicardial adipose tissue (EAT) thickness may act as a therapeutic target during treatments with drugs modulating the adipose tissue. We evaluate EAT thickness in RA patients treated with biological and nonbiological disease-modifying antirheumatic drugs (DMARDs). A cross-sectional study was conducted with a cohort of 34 female RA patients and 16 controls matched for age and body mass index (BMI). Plasma glucose, basal insulin, plasma lipids, and high-sensitivity C-reactive protein (hs-CRP) were assessed. EAT thickness and left ventricular mass (LVM) were measured by echocardiography. No significant differences in waist circumference (WC), blood pressure, fasting blood glucose, basal insulin, and lipid parameters were found between the groups. The control group showed lower concentrations (P=0.033) of hs-CRP and LVM (P=0.0001) than those of the two RA groups. Patients treated with TNF-α inhibitors showed significantly lower EAT thickness than those treated with nonbiological DMARDs (8.56 ± 1.90 mm versus 9.71 ± 1.45 mm; P=0.04). Women with no RA revealed reduced EAT thickness (5.39 ± 1.52 mm) as compared to all RA patients (P=0.001). Results suggest that RA patients have greater EAT thickness than controls regardless of BMI and WC.

Acute exposure to diesel-biodiesel particulate matter promotes murine lung oxidative stress by Nrf2/HO-1 and inflammation through the NF-κB/TNF-α pathways

2017 ◽  
Vol 112 ◽  
pp. 201
Author(s):  
Samuel dos Santos Valenca ◽  
Isabella Cattani-Cavalieri ◽  
Giovanna Marcella Cavalcante Carvalho ◽  
Walter Araújo Zin ◽  
Andréa Monte Alto Costa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Particulate Matter ◽  
Acute Exposure ◽  
Murine Lung ◽  
Tnf Α ◽  
Lung Oxidative Stress

scholarly journals Fasudil attenuates Neuro-Inflammation and Oxidative Stress via Rhoa/Rock Pathways in Delayed Neuropsychologic Sequelae Mice Model

2021 ◽  
Author(s):  
Xiang Yan ◽  
Meng Fu ◽  
Ye Gao ◽  
Qin Han ◽  
Shuang Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuroprotective Effect ◽  
Carbon Monoxide Poisoning ◽  
Immunofluorescence Staining ◽  
Control Group ◽  
Spatial Learning And Memory ◽  
Mrna Levels ◽  
Co Poisoning ◽  
Mice Model ◽  
Tnf Α

Abstract Background Delayed neuropsychologic sequelae is common in patients after carbon monoxide poisoning without effective methods worldwide. Fasudil exerts neuroprotective effect and alleviates oxidative stress in some neurodegenerative disorders. However, the mechanism between DNS and FS remains unclear. The study aims to explore the efficacy and mechanism of Fasudil in DNS mice model. Objective The delayed neuropsychologic sequelae model was induced with a hyperbaric oxygen chamber. All rats were randomly assigned to three groups (n=10): air control group (AC), CO poisoning group (CO), and CO poisoning +Fasudil group (CO+FS). Rats in the CO+FS group were given Fasudil (10 mg/kg/day, ip). The morris water maze was documented to estimate spatial learning and memory of mice. The demyelination state in brain was observed through LFB staining. The protein of MBP was examined with immunofluorescence staining. The levels of IL-6, TNF-α, TGF-β, SOD, and MDA were examined by ELISA. The mRNA levels of Rho, ROCK2, MLC1 and MYPT1 were analyzed by rt-PCR. Result The cognitive impairment in the CO+FS group were significantly reduced than those of the CO group (P<0.05). LFB staining and immunofluorescence staining of MBP results showed that FS significantly treatment attenuated demyelination (P<0.05). Compared with the CO group, the levels of TNF-α, IL-6, MDA, ROCK2, MLC1, and MYPT1 significantly decreased (P<0.05), and the levels of SOD were significantly increased in the CO+FS group (P<0.05). Conclusion In a word, Fasudil attenuated delayed neuropsychologic sequelae by inhibiting inflammation, oxidative stress and downregulating Rho/ROCK pathway in DNS mice model. We conclude that Fasudil may be a novel treatment for delayed neuropsychologic sequelae.

Hemorrhage-induced α-adrenergic signaling results in myocardial TNF-α expression and contractile dysfunction

2001 ◽  
Vol 281 (1) ◽  
pp. H84-H92 ◽  
Author(s):  
Rohan Shahani ◽  
Lazar V. Klein ◽  
John G. Marshall ◽  
Sherwin Nicholson ◽  
Barry B. Rubin ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Neutralizing Antibody ◽  
Multiple Organ ◽  
Left Ventricular ◽  
Enzyme Linked Immunosorbent Assay ◽  
Adrenergic Blockade ◽  
Adrenergic Stimulation ◽  
Tnf Α ◽  
Factor Α

Hemorrhagic shock (HS), secondary to major blood loss, frequently precedes multiple organ dysfunction and is accompanied by a surge in circulating catecholamine levels. Expression of the cardiodepressant cytokine, tumor necrosis factor-α (TNF-α), has been observed in the heart after HS and resuscitation (HS/R) and α1-adrenergic blockade prevented translocation of the nuclear transcription factor, NF-κB, to the nucleus. We hypothesized that α1-adrenergic stimulation induces myocardial TNF-α expression, which results in depressed cardiac function after HS/R. The role of α1-adrenergic stimulation in myocardial TNF-α expression and depressed cardiac function after HS/R was assessed by treatment with the α1-adrenergic inhibitor, prazosin hydrochloride (1 mg/kg ip), for 1 h before the onset of hemorrhage. In addition, TNF-α was neutralized with a specific antibody (600 μl/kg iv) 5 min before hemorrhage. HS was induced by the withdrawal of blood to a mean blood pressure of 50 mmHg for 1 h. Contractile function was measured with the use of a Langendorff apparatus 2 h after the end of HS. HS/R led to significant decreases in left ventricular developed tension and in the maximal rate of pressure increase over time during both contraction and relaxation. Myocardial expression of TNF-α measured by enzyme-linked immunosorbent assay increased significantly after 30 min of hemorrhage and peaked after 60 min of HS and 45 min of resuscitation. Depression in cardiac function after HS/R was reversed by 85% in hearts from rats treated with a TNF-α neutralizing antibody and by 90% in hearts from rats treated with prazosin hydrochloride. We conclude that HS activates a α1-adrenergic pathway, resulting in TNF-α expression in the heart and depressed myocardial contractile function.

Dynorphin, naloxone, and overflow of norepinephrine during cardiac nerve stimulation in dogs

1992 ◽  
Vol 263 (1) ◽  
pp. H153-H161 ◽  
Author(s):  
H. Gu ◽  
B. A. Barron ◽  
J. F. Gaugl ◽  
J. L. Caffrey
Keyword(s):  
Nerve Stimulation ◽  
Myocardial Contractility ◽  
Contractile Function ◽  
Time Derivative ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Endogenous Opioids ◽  
Control Group ◽  
Cardiac Nerve ◽  
Mediated Effects

The effects of dynorphin-(1-9) and naloxone on norepinephrine (NE) overflow and myocardial contractility were determined during left cardiac nerve stimulation in the anesthetized dog. Stimulation-induced increases in NE overflow from the left ventricle were monitored during control conditions, during infusion of dynorphin-(1-9), during dynorphin plus naloxone, and after naloxone alone. Four electrical stimulations were applied for 1 min at 20-min intervals. Repeated left cardiac nerve stimulations (control group) reduced stimulated NE overflow 50-60% by 1 h. If stimulations were only conducted at 0 and 1 h, the decline in NE overflow was not observed. Intracoronary dynorphin (2 nmol.min-1.kg-1, 20 min) lowered the stimulation-induced increase in NE overflow further and reduced first time derivative of left ventricular pressure (dP/dt) and myocardial O2 consumption responses. Naloxone (100 micrograms/kg) prevented all of the dynorphin-mediated effects. When given alone, naloxone increased both NE overflow and left ventricular dP/dt during stimulation and prevented or significantly delayed the gradual decline in overflow observed in stimulated controls. A postjunctional effect of dynorphin was evaluated by comparing contractile responses to the intracoronary infusion of NE before and during dynorphin. Dynorphin did not alter contractile function at rest or during NE infusion. In summary, dynorphin-(1-9) depresses nerve stimulation-induced, cardiac NE overflow, and myocardial contractility in a naloxone-reversible fashion. Alone, naloxone appears to regulate stimulated NE overflow through a qualitatively different mechanism. Endogenous opioids may normally moderate myocardial function during cardiac nerve stimulation by regulating junctional NE concentrations through a combination of effects on NE release and/or its subsequent reuptake.

Nicorandil reduces myocardial injury and improves cardiac function in valve replacement surgery.

2019 ◽  
Vol 1 (4) ◽  
pp. 120-126
Author(s):  
Wael Elfeky ◽  
Mohamed Aboelnasr ◽  
Ayman Sallam ◽  
Wael Haseeb ◽  
Dalia R El-Afify
Keyword(s):  
Valve Replacement ◽  
Myocardial Protection ◽  
Myocardial Injury ◽  
Troponin I ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Replacement Surgery ◽  
Tnf Α ◽  
Valve Replacement Surgery

Background: Myocardial injury during cardiac surgery is associated with increased morbidity and mortality, and proper myocardial protection improves surgical outcomes. We aimed to study the role of preoperative nicorandil in myocardial protection during valve replacement surgery. Methods: The study included 40 patients who were randomized into two groups: control group, and nicorandil group. Preoperative, intraoperative, and postoperative data were collected. Creatine kinase- MB (CK-MB), troponin I, malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured 24-hours before surgery then 4, 12 and 48 hours after aortic cross-clamp removal. Results: Nicorandil significantly decreased MDA (p=0.005 and 0.036), TNF-α (p< 0.001), IL-6 (p<0.001 and 0.003) 4 and 12 hours following the removal of aortic clamp compared to the control group. Additionally, It significantly reduced CK-MB (p< 0.0001 and 0.0002) and troponin-I (p= 0.0002 and < 0.0001) 4 and 12 hours after the removal of the aortic clamp, respectively. However, there was no significant difference in MDA, TNF-α, IL-6, CK-MB, and troponin-I levels between the nicorandil and the control group after 48 hours following the removal of aortic clamping (p= 0.084; 0.64; 0.12; 0.12; 0.75; respectively). Conclusions: Nicorandil reduced myocardial injury significantly in valve replacement surgery. Nicorandil decreased CK-MB and troponin I and improved postoperative left ventricular ejection fraction.

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