scholarly journals A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation

2008 ◽  
Vol 294 (6) ◽  
pp. H2775-H2784 ◽  
Author(s):  
Peter J. Leary ◽  
Surender Rajasekaran ◽  
R. Ray Morrison ◽  
Elaine I. Tuomanen ◽  
Thomas K. Chin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Platelet Activating Factor ◽  
Receptor Activation ◽  
Protective Effects ◽  
Loss Of Function ◽  
Wild Type ◽  
Intracellular Ca ◽  
Paf Receptor

Controversy exists as to whether platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, can actually protect the heart from postischemic injury. To determine whether endogenous activation of the PAF receptor is cardioprotective, we examined postischemic functional recovery in isolated hearts from wild-type and PAF receptor-knockout mice. Postischemic function was reduced in hearts with targeted deletion of the PAF receptor and in wild-type hearts treated with a PAF receptor antagonist. Furthermore, perfusion with picomolar concentrations of PAF improved postischemic function in hearts from wild-type mice. To elucidate the mechanism of a PAF-mediated cardioprotective effect, we employed a model of intracellular Ca2+ overload and loss of function in nonischemic ventricular myocytes. We found that PAF receptor activation attenuates the time-dependent loss of shortening and increases in intracellular Ca2+ transients in Ca2+-overloaded myocytes. These protective effects of PAF depend on nitric oxide, but not activation of cGMP. In addition, we found that reversible S-nitrosylation of myocardial proteins must occur in order for PAF to moderate Ca2+ overload and loss of myocyte function. Thus our data are consistent with the hypothesis that low-level PAF receptor activation initiates nitric oxide-induced S-nitrosylation of Ca2+-handling proteins, e.g., L-type Ca2+ channels, to attenuate Ca2+ overload during ischemia-reperfusion in the heart. Since inhibition of the PAF protective pathway reduces myocardial postischemic function, our results raise concern that clinical therapies for inflammatory diseases that lead to complete blockade of the PAF receptor may eliminate a significant, endogenous cardioprotective pathway.

Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury

1997 ◽  
Vol 273 (3) ◽  
pp. L504-L512 ◽  
Author(s):  
Y. C. Huang ◽  
P. W. Fisher ◽  
E. Nozik-Grayck ◽  
C. A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Average Rate ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
No Production ◽  
Protective Effects ◽  
Lung Weight ◽  
Edema Formation ◽  
No Donors

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

scholarly journals Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jian-Ping Zhang ◽  
Wei-Jing Zhang ◽  
Miao Yang ◽  
Hua Fang
Keyword(s):  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

Efficacy of Nitric Oxide Administration in Attenuating Ischemia/Reperfusion Injury During Neonatal Cardiopulmonary Bypass

2020 ◽  
Vol 11 (4) ◽  
pp. 417-423 ◽  
Author(s):  
Chawki Elzein ◽  
Cynthia Urbas ◽  
Bonnie Hughes ◽  
Yi Li ◽  
Cheryl Lefaiver ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiopulmonary Bypass ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Controlled Trial ◽  
Postoperative Recovery ◽  
Norwood Procedure ◽  
Protective Effects ◽  
Aortic Cross Clamp Time ◽  
To Receive

Objective: Nitric oxide (NO) plays several protective roles in ischemia/reperfusion (I/R) injury. Neonates undergoing the Norwood procedure are subject to develop I/R injury due to the immaturity of their organs and the potential need to interrupt or decrease systemic flow during surgery. We hypothesized that NO administration during cardiopulmonary bypass (CPB) ameliorates the I/R and could help the postoperative recovery after the Norwood procedure. Methods: Twenty-four neonates who underwent a Norwood procedure were enrolled in a prospective randomized blinded controlled trial to receive NO (12 patients) or placebo (12 patients) into the oxygenator of the CPB circuit during the Norwood procedure. Markers of I/R injury were collected at baseline (T0), after weaning from CPB before modified ultrafiltration (T1), after modified ultrafiltration (T2), and at 12 hours (T3) and 24 hours (T4) after surgery, and they were compared between both groups, as well as other postoperative clinical variables. Results: There was no difference in age, weight, anatomical diagnosis, CPB, and aortic cross-clamp time between both groups. Troponin levels were lower in the study group at T1 (0.62 ± 58 ng/mL vs 0.87 ± 0.58 ng/mL, P = .31) and became significantly lower at T2 (0.36 ± 0.32 ng/mL vs 0.97 ± 0.48 ng/mL, P = .009).There were no significant differences between both groups for all other markers. Despite a lower troponin level, there was no difference in inotropic scores or ventricular function between both groups. Time to start diuresis, time to sternal closure and extubation, and intensive care unit and hospital stay were not different between both groups. Conclusion: Systemic administration of NO during the Norwood procedure has myocardial protective effects (lower Troponin levels) but we observed no effect on postoperative recovery. Larger sample size may be needed to show clinical differences.

Protective Effect of Nitric Oxide Pathway in L-Citrulline Renal Ischemia-Reperfusion Injury in Rats

2013 ◽  
Vol 634-638 ◽  
pp. 1357-1361
Author(s):  
Xin Ling ◽  
Xiao Bin Fu ◽  
Li Liu ◽  
Xia Tian ◽  
Ling Yan Sun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Renal Cortex ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Protective Effects ◽  
Significant Protection ◽  
Renal Ischemia Reperfusion Injury ◽  
Reperfusion Period ◽  
Oxide Synthase

To observe the protective effects of L-citrulline on the renal ischemia-reperfusion (I/R) injury and elucidate the mechanisms involved. Forty-eight rats were randomized into eight groups. At the end of the reperfusion period, serum was collected and the kidneys were removed for histological and biochemical examinations. Our results showed that pretreatment with L-citrulline significantly ameliorated the renal injury caused by I/R. Moreover, L-citrulline increased the levels of NO. The I/R-induced decreases in total nitric oxide synthase (NOS) activity, inducible NOS activity and constitutive NOS activity in the renal cortex were significantly prevented. These results suggested that L-citrulline administration exhibited significant protection on renal I/R injury.

scholarly journals PDGF receptor-β modulates metanephric mesenchyme chemotaxis induced by PDGF AA

2009 ◽  
Vol 296 (2) ◽  
pp. F406-F417 ◽  
Author(s):  
Jill M. Ricono ◽  
Brent Wagner ◽  
Yves Gorin ◽  
Mazen Arar ◽  
Andrius Kazlauskas ◽  
...  
Keyword(s):  
Cell Migration ◽  
Kidney Development ◽  
Receptor Activation ◽  
Ros Generation ◽  
Pdgf Receptor ◽  
Metanephric Mesenchyme ◽  
Wild Type ◽  
Intracellular Ca ◽  
Β Receptor ◽  
In Cells

PDGF B chain or PDGF receptor (PDGFR)-β-deficient (−/−) mice lack mesangial cells. To study responses of α- and β-receptor activation to PDGF ligands, metanephric mesenchymal cells (MMCs) were established from embryonic day E11.5 wild-type (+/+) and −/− mouse embryos. PDGF BB stimulated cell migration in +/+ cells, whereas PDGF AA did not. Conversely, PDGF AA was chemotactic for −/− MMCs. The mechanism by which PDGFR-β inhibited AA-induced migration was investigated. PDGF BB, but not PDGF AA, increased intracellular Ca2+ and the production of reactive oxygen species (ROS) in +/+ cells. Transfection of −/− MMCs with the wild-type β-receptor restored cell migration and ROS generation in response to PDGF BB and inhibited AA-induced migration. Inhibition of Ca2+ signaling facilitated PDGF AA-induced chemotaxis in the wild-type cells. The antioxidant N-acetyl-l-cysteine (NAC) or the NADPH oxidase inhibitor diphenyleneiodonium (DPI) abolished the BB-induced increase in intracellular Ca2+ concentration, suggesting that ROS act as upstream mediators of Ca2+ in suppressing PDGF AA-induced migration. These data indicate that ROS and Ca2+ generated by active PDGFR-β play an essential role in suppressing PDGF AA-induced migration in +/+ MMCs. During kidney development, PDGFR β-mediated ROS generation and Ca2+ influx suppress PDGF AA-induced chemotaxis in metanephric mesenchyme.

Prevention of ischemia-reperfusion lung injury by inhaled nitric oxide in neonatal piglets

1996 ◽  
Vol 80 (3) ◽  
pp. 782-788 ◽  
Author(s):  
F. Barbotin-Larrieu ◽  
M. Mazmanian ◽  
B. Baudet ◽  
H. Detruit ◽  
A. Chapelier ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Neutrophil Accumulation ◽  
Pulmonary Endothelium ◽  
Neonatal Piglets ◽  
Neonatal Piglet ◽  
Pulmonary Arterial ◽  
Coefficient Of Filtration

Lung ischemia-reperfusion results in a decrease in the release of nitric oxide (NO) by the pulmonary endothelium. NO may have lung-protective effects by decreasing neutrophil accumulation in the lung. We tested whether NO inhalation would attenuate reperfusion-induced endothelial dysfunction and increases in microvascular permeability and total pulmonary vascular resistance (RT) by preventing neutrophil lung accumulation. After baseline determinations of RT, coefficient of filtration (Kfc), and circulating neutrophil counts, isolated neonatal piglet lungs were subjected to a 1-h period of ischemia followed by a 1-h period of blood reperfusion and reventilation with or without addition of NO (10 ppm). NO prevented reperfusion-induced increases in RT and Kfc, as well as the decrease in circulating neutrophils. After reperfusion, increases in Kfc were correlated with decreases in circulating neutrophils. NO prevented reperfusion-induced decrease in endothelium-dependent relaxation in precontracted pulmonary arterial rings. This demonstrates that inhaled NO prevents microvascular injury, endothelial dysfunction, and pulmonary neutrophil accumulation in a neonatal piglet model of lung ischemia-reperfusion.

scholarly journals Update on the Role of Cannabinoid Receptors after Ischemic Stroke

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Luciano S. A. Capettini ◽  
Silvia Q. Savergnini ◽  
Rafaela F. da Silva ◽  
Nikos Stergiopulos ◽  
Robson A. S. Santos ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cannabinoid Receptors ◽  
Inflammatory Diseases ◽  
Receptor Activation ◽  
Protective Effects ◽  
Peripheral Tissues ◽  
Transmembrane Receptors ◽  
Anti Inflammatory

Cannabinoids are considered as key mediators in the pathophysiology of inflammatory diseases, including atherosclerosis. In particular, they have been shown to reduce the ischemic injury after acute cardiovascular events, such as acute myocardial infarction and ischemic stroke. These protective and anti-inflammatory properties on peripheral tissues and circulating inflammatory have been demonstrated to involve their binding with both selective cannabinoid type 1 (CB1) and type 2 (CB2) transmembrane receptors. On the other hands, the recent discoveries of novel different classes of cannabinoids and receptors have increased the complexity of this system in atherosclerosis. Although only preliminary data have been reported on the activities of novel cannabinoid receptors, several studies have already investigated the role ofCB1andCB2receptors in ischemic stroke. WhileCB1receptor activation has been shown to directly reduce atherosclerotic plaque inflammation, controversial data have been shown on neurotransmission and neuroprotection after stroke. Given its potent anti-inflammatory activities on circulating leukocytes, theCB2activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke.

scholarly journals Protective Effects of Millettia Pulchra Flavonoids on Myocardial Ischemia In Vitro and In Vivo

2015 ◽  
Vol 35 (2) ◽  
pp. 516-528 ◽  
Author(s):  
Jianchun Huang ◽  
Xudong Zhang ◽  
Feizhang Qin ◽  
Yingxin Li ◽  
Xiaoqun Duan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Protective Effects ◽  
Bax Protein ◽  
Oxide Synthase

Background: Previous studies have demonstrated that Millettia pulchra flavonoids (MPF) exhibit protective effects on myocardial ischemia reperfusion injury (MI/RI) in isolated rat hearts and show anti-oxidative, anti-hypoxic and anti-stress properties. Methods: In this study, the cardioprotective effects of MPF on myocardial ischemia and its underlying mechanisms were investigated by a hypoxia/ reoxygenation (H/R) injury model in vitro and a rat MI/RI model in vivo. Results: We found that the lactate dehydrogenase (LDH) and inducible nitric oxide synthase (iNOS) activities were decreased in the MPF pretreatment group, whereas the activities of constructional nitric oxide synthase (cNOS), total nitric oxide synthase (tNOS), Na+-K+-ATPase and Ca2+-Mg2+-ATPase were significantly increased. In addition, the cardiocytes were denser in the MPF groups than in the control group. The mortality rate and apoptosis rate of cardiocytes were significantly decreased. Furthermore, pretreatment with MPF in vivo significantly improved the hemodynamics, decreased malondialdehyde (MDA) abundance, increased the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the expression of the Bax protein and ratio Bax/Bc1-2 ration. Conclusions: These results suggest that MPF is an attractive protective substance in myocardial ischemia due to its negative effects on heart rate and ionotropy, reduction of myocardial oxidative damage and modulation of gene expression associated with apoptosis.

scholarly journals Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion

2014 ◽  
Vol 306 (7) ◽  
pp. H1066-H1077 ◽  
Author(s):  
JuFang Wang ◽  
Jianliang Song ◽  
Erhe Gao ◽  
Xue-Qian Zhang ◽  
Tongda Gu ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Wild Type ◽  
Protein Levels ◽  
Plasmic Reticulum ◽  
Intracellular Ca ◽  
Similar Survival

Phospholemman (PLM), when phosphorylated at Ser68, inhibits cardiac Na+/Ca2+ exchanger 1 (NCX1) and relieves its inhibition on Na+-K+-ATPase. We have engineered mice in which expression of the phosphomimetic PLM S68E mutant was induced when dietary doxycycline was removed at 5 wk. At 8–10 wk, compared with noninduced or wild-type hearts, S68E expression in induced hearts was ∼35–75% that of endogenous PLM, but protein levels of sarco(endo)plasmic reticulum Ca2+-ATPase, α1- and α2-subunits of Na+-K+-ATPase, α1c-subunit of L-type Ca2+ channel, and phosphorylated ryanodine receptor were unchanged. The NCX1 protein level was increased by ∼47% but the NCX1 current was depressed by ∼34% in induced hearts. Isoproterenol had no effect on NCX1 currents but stimulated Na+-K+-ATPase currents equally in induced and noninduced myocytes. At baseline, systolic intracellular Ca2+ concentrations ([Ca2+]i), sarcoplasmic reticulum Ca2+ contents, and [Ca2+]i transient and contraction amplitudes were similar between induced and noninduced myocytes. Isoproterenol stimulation resulted in much higher systolic [Ca2+]i, sarcoplasmic reticulum Ca2+ content, and [Ca2+]i transient and contraction amplitudes in induced myocytes. Echocardiography and in vivo close-chest catheterization demonstrated similar baseline myocardial function, but isoproterenol induced a significantly higher +dP/d t in induced compared with noninduced hearts. In contrast to the 50% mortality observed in mice constitutively overexpressing the S68E mutant, induced mice had similar survival as wild-type and noninduced mice. After ischemia-reperfusion, despite similar areas at risk and left ventricular infarct sizes, induced mice had significantly higher +dP/d t and −dP/d t and lower perioperative mortality compared with noninduced mice. We propose that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease.

Sign in / Sign up

Export Citation Format

Share Document