Endothelial nitric oxide synthase (NOS3) knockout decreases NOS2 induction, limiting hyperoxygenation and conferring protection in the postischemic heart

2007 ◽  
Vol 292 (3) ◽  
pp. H1541-H1550 ◽  
Author(s):  
Xue Zhao ◽  
Yeong-Renn Chen ◽  
Guanglong He ◽  
Aiwen Zhang ◽  
Lawrence J. Druhan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Infarct Size ◽  
Endothelial Nitric Oxide Synthase ◽  
Nadh Dehydrogenase ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Postischemic Myocardium ◽  
Inos Induction

Although it has been shown that endothelial nitric oxide synthase (eNOS)-derived nitric oxide downregulates mitochondrial oxygen consumption during early reperfusion, its effects on inducible NOS (iNOS) induction and myocardial injury during late reperfusion are unknown. Wild-type (WT) and eNOS−/− mice were subjected to 30 min of coronary ligation followed by reperfusion. Expression of iNOS mRNA and protein levels and peroxynitrite production were lower in postischemic myocardium of eNOS−/− mice than levels in WT mice 48 h postreperfusion. Significantly improved hemodynamics (±dP/d t, left ventricular systolic pressure, mean arterial pressure), increased rate pressure product, and reduced myocardial infarct size (18 ± 2.5% vs. 31 ± 4.6%) were found 48 h after reperfusion in eNOS−/− mice compared with WT mice. Myocardial infarct size was also significantly decreased in WT mice treated with the specific iNOS inhibitor 1400W (20.5 ± 3.4%) compared with WT mice treated with PBS (33.9 ± 5.3%). A marked reperfusion-induced hyperoxygenation state was observed by electron paramagnetic resonance oximetry in postischemic myocardium, but Po2 values were significantly lower from 1 to 72 h in eNOS−/− than in WT mice. Cytochrome c-oxidase activity and NADH dehydrogenase activity were significantly decreased in postischemic myocardium in WT and eNOS−/− mice compared with baseline control, respectively, and NADH dehydrogenase activity was significantly higher in eNOS−/− than in WT mice. Thus deficiency of eNOS exerted a sustained beneficial effect on postischemic myocardium 48 h after reperfusion with preserved mitochondrial function, which appears to be due to decreased iNOS induction and decreased iNOS-derived peroxynitrite in postischemic myocardium.

scholarly journals Isoflurane Favorably Modulates Guanosine Triphosphate Cyclohydrolase-1 and Endothelial Nitric Oxide Synthase during Myocardial Ischemia and Reperfusion Injury in Rats

2015 ◽  
Vol 123 (3) ◽  
pp. 582-589 ◽  
Author(s):  
Ines Baotic ◽  
Dorothee Weihrauch ◽  
Jesse Procknow ◽  
Jeanette Vasquez-Vivar ◽  
Zhi-Dong Ge ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Infarct Size ◽  
Endothelial Nitric Oxide Synthase ◽  
Myocardial Infarct ◽  
No Production ◽  
Myocardial Infarct Size ◽  
Ischemia And Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Abstract Background: The authors investigated the hypothesis that isoflurane modulates nitric oxide (NO) synthesis and protection against myocardial infarction through time-dependent changes in expression of key NO regulatory proteins, guanosine triphosphate cyclohydrolase (GTPCH)-1, the rate-limiting enzyme involved in the biosynthesis of tetrahydrobiopterin and endothelial nitric oxide synthase (eNOS). Methods: Myocardial infarct size, NO production (ozone-mediated chemiluminescence), GTPCH-1, and eNOS expression (real-time reverse transcriptase polymerase chain reaction and western blotting) were measured in male Wistar rats with or without anesthetic preconditioning (APC; 1.0 minimum alveolar concentration isoflurane for 30 min) and in the presence or absence of an inhibitor of GTPCH-1, 2,4-diamino-6-hydroxypyrimidine. Results: NO−2 production (158 ± 16 and 150 ± 13 pmol/mg protein at baseline in control and APC groups, respectively) was significantly (P < 0.05) increased 1.5 ± 0.1 and 1.4 ± 0.1 fold by APC (n = 4) at 60 and 90 min of reperfusion, respectively, concomitantly, with increased expression of GTPCH-1 (1.3 ± 0.3 fold; n = 5) and eNOS (1.3 ± 0.2 fold; n = 5). In contrast, total NO (NO−2 and NO−3) was decreased after reperfusion in control experiments. Myocardial infarct size was decreased (43 ± 2% of the area at risk for infarction; n = 6) by APC compared with control experiments (57 ± 1%; n = 6). 2, 4-Diamino-6-hydroxypyrimidine decreased total NO production at baseline (221 ± 25 and 175 ± 31 pmol/mg protein at baseline in control and APC groups, respectively), abolished isoflurane-induced increases in NO at reperfusion, and prevented reductions of myocardial infarct size by APC (60 ± 2%; n = 6). Conclusion: APC favorably modulated a NO biosynthetic pathway by up-regulating GTPCH-1 and eNOS, and this action contributed to protection of myocardium against ischemia and reperfusion injury.

scholarly journals Relaxin Peptide Hormones Are Protective During the Early Stages of Ischemic Stroke in Male Rats

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 638-646 ◽  
Author(s):  
Lindsay H. Bergeron ◽  
Jordan M. Willcox ◽  
Faisal J. Alibhai ◽  
Barry J. Connell ◽  
Tarek M. Saleh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Nitric Oxide Synthase ◽  
Infarct Size ◽  
Endothelial Nitric Oxide Synthase ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Protective Mechanisms ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The pregnancy hormone relaxin protects tissue from ischemic damage. The ability of relaxin-3, a relaxin paralog, to do so has not been explored. The cerebral expression levels of these peptides and their receptors make them logical targets for study in the ischemic brain. We assessed relaxin peptide-mediated protection, relative relaxin family peptide receptor (RXFP) involvement, and protective mechanisms. Sprague-Dawley rats receiving permanent (pMCAO) or transient middle cerebral artery occlusions (tMCAO) were treated with relaxin peptides, and brains were collected for infarct analysis. Activation of the endothelial nitric oxide synthase pathway was evaluated as a potential protective mechanism. Primary cortical rat astrocytes were exposed to oxygen glucose deprivation and treated with relaxin peptides, and viability was examined. Receptor involvement was explored using RXFP3 antagonist or agonist treatment and real-time PCR. Relaxin and relaxin-3 reduced infarct size after pMCAO. Both peptides activated endothelial nitric oxide synthase. Because relaxin-3 has not previously been associated with this pathway and displays promiscuous RXFP binding, we explored the receptor contribution. Expression of rxfp1 was greater than that of rxfp3 in rat brain, although peptide binding at either receptor resulted in similar overall protection after pMCAO. Only RXFP3 activation reduced infarct size after tMCAO. In astrocytes, rxfp3 gene expression was greater than that of rxfp1. Selective activation of RXFP3 maintained astrocyte viability after oxygen glucose deprivation. Relaxin peptides are protective during the early stages of ischemic stroke. Differential responses among treatments and models suggest that RXFP1 and RXFP3 initiate different protective mechanisms. This preliminary work is a pivotal first step in identifying the clinical implications of relaxin peptides in ischemic stroke.

Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction

2010 ◽  
Vol 298 (4) ◽  
pp. H1198-H1208 ◽  
Author(s):  
Kyle T. Keyes ◽  
Jing Xu ◽  
Bo Long ◽  
Congfang Zhang ◽  
Zhaoyong Hu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Left Ventricular Function ◽  
Infarct Size ◽  
Caspase 3 ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Pharmacological Inhibition ◽  
Oxide Synthase

Phosphoinositide 3-kinase (PI3K) mediates myocardium protective signaling through phosphorylation of phosphatidylinositol (Ptdins) to produce Ptdins(3,4,5)P3. Lipid phosphatase and tensin homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating Ptdins(3,4,5)P3; therefore, the inhibition of PTEN enhances PI3K/Akt signaling and could prevent myocardium from ischemia-reperfusion (I/R) injury. Here we studied 1) whether the pharmacological inhibition of PTEN by bisperoxovanadium molecules [BpV(HOpic)] attenuates simulated I/R (SIR) injury in vitro and 2) whether the administration of BpV(HOpic) either before or after ischemia limits myocardial infarct size (IS) and ameliorates cardiodysfunction caused by infarction. First, adult rat cardiomyocytes were treated with or without BpV(HOpic) and then exposure to SIR. Second, anesthetized rats received BpV(HOpic) either before or after ischemia. IS was assessed at 4 h reperfusion, and left ventricular function was evaluated by echocardiography at 28 days postreperfusion. As a result, BpV(HOpic) decreased cell death, improved 3-[4,5-yl]-2,5-diphenyltetrazolium bromide (MTT) viability, and reduced apoptosis in cells exposed to SIR. These protective effects of BpV(HOpic) are associated with increased phospho-Akt and the repression of caspase-3 activity. Second, the administration of BpV(HOpic) significantly reduced IS and suppressed caspase-3 activity following I/R injury and consequentially improved cardiac function at 28 day postinfarction. These beneficial effects of BpV(HOpic) are attributed to increases in myocardial levels of phosphorylation of Akt/endothelial nitric oxide synthase (eNOS), ERK-1/2, and calcium-dependent nitric oxide synthase activity. In conclusion, the pharmacological inhibition of PTEN protects against I/R injury through the upregulation of the PI3K/Akt/eNOS/ERK prosurvival pathway, suggesting a new therapeutic strategy to combat I/R injury.

Desflurane-induced Preconditioning against Myocardial Infarction Is Mediated by Nitric Oxide

2006 ◽  
Vol 105 (4) ◽  
pp. 719-725 ◽  
Author(s):  
Thorsten M. Smul ◽  
Markus Lange ◽  
Andreas Redel ◽  
Natalie Burkhard ◽  
Norbert Roewer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Nitric Oxide Synthase Inhibitor ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Nitric Oxide Synthase Activity

Background Volatile anesthetics induce myocardial preconditioning through a signal transduction pathway that is remarkably similar to that observed during ischemic preconditioning. Nitric oxide-dependent signaling plays an important role in anesthetic and ischemic preconditioning. Therefore, the authors tested the hypothesis that desflurane-induced preconditioning is mediated by nitric oxide. Methods Barbiturate-anesthetized rabbits were instrumented for measurement of hemodynamics. All rabbits were subjected to 30-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size was assessed with triphenyltetrazolium chloride staining. Myocardial nitric oxide synthase activity was assessed with a [H]L-arginine-conversion assay. Rabbits were randomized to five separate experimental groups. They received 0.0 or 1.0 minimum alveolar concentration desflurane for 30 min, which was discontinued 30 min before ischemia in the absence or presence of the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA). L-NA was given either 20 min before or 10 min after desflurane administration, respectively. Data are mean +/- SEM. Results Infarct size was 56 +/- 8% in control experiments. Desflurane significantly (P < 0.05) reduced infarct size to 35 +/- 4%. Preconditioning by desflurane was totally blocked by administration of L-NA either during or after desflurane inhalation (58 +/- 4 and 59 +/- 9%, respectively). L-NA alone had no effect on infarct size (56 +/- 7%). Nitric oxide synthase activity was significantly (P < 0.05) increased by desflurane. Conclusion The results demonstrate that desflurane-induced preconditioning markedly reduced myocardial infarct size. This beneficial effect was blocked by the nitric oxide synthase inhibitor L-NA either during or after desflurane-administration. These data suggest that early desflurane-induced preconditioning is mediated by nitric oxide.

Abstract WP296: Short Term Acute Preconditioning Exercise Improves Stroke Outcomes and Reduces Neurovascular Injury via Increased Endothelial Nitric Oxide Synthase Activity

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Sherif Hafez ◽  
Mohammad B Khan ◽  
Jesse D Wagner ◽  
David C Hess
Keyword(s):  
Nitric Oxide ◽  
Infarct Size ◽  
Endothelial Nitric Oxide Synthase ◽  
Acute Exercise ◽  
Short Term ◽  
Stroke Outcomes ◽  
Enos Activity ◽  
Exercise Induced ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Physical exercise is becoming a prominent therapeutic strategy to improve stroke outcomes. It was previously shown that long term exercise reduces infarct volume, but this was never tested in acute short term preconditioning exercise in a thromboembolic model of stroke. Exercise induced shear stress improves vascular function through increased activity of endothelial nitric oxide synthase (eNOS) and its upstream principal activator, AMP-activated protein kinase (AMPK). However, this was not previously tested in a stroke setting. Accordingly, we tested the hypothesis that acute short term preconditioning exercise improves stroke outcomes through increased AMPK and eNOS activity. Methods: Male Wistar rats (300g) were subjected to treadmill exercise for four days (25 minutes/day), break for 2 days and then one acute bout for 30 minutes. Exercised animals were subjected to thromboembolic stroke at 1h, 6h or 24h after the last exercise session. At 24h, control (sedentary) and exercised rats were tested for neurological outcomes, infarct size and edema. Western Blotting was used to measure the expression of active eNOS (p-S1177-eNOS) and active AMPK (p-T172-AMPK). Results: Acute exercise significantly reduced infarct size and edema and improved functional outcomes compared to control. It also significantly increased the expression of peNOS and pAMPK in the brain, cerebral vessels and aorta (Table). Conclusion: Acute exercise preconditioning significantly reduced neurovascular injury and improved functional outcome after stroke through increased eNOS activity. Our findings are novel to point out the role of preconditioning exercise induced AMPK and eNOS activation in improving stroke outcomes.

Endothelial nitric oxide synthase overexpression attenuates myocardial reperfusion injury

2004 ◽  
Vol 286 (1) ◽  
pp. H276-H282 ◽  
Author(s):  
Steven P. Jones ◽  
James J. M. Greer ◽  
Aman K. Kakkar ◽  
P. Derek Ware ◽  
Richard H. Turnage ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Left Ventricular ◽  
Myocardial Reperfusion ◽  
Enos Gene ◽  
Myocardial Infarct Size ◽  
Endothelial Nitric Oxide ◽  
Fractional Shortening

Previous studies indicate that deficiency of endothelial nitric oxide (NO) synthase (eNOS)-derived NO exacerbates myocardial reperfusion injury. We hypothesized that overexpression of eNOS would reduce the extent of myocardial ischemia-reperfusion (MI/R) injury. We investigated two distinct strains of transgenic (TG) mice overexpressing the eNOS gene (eNOS TG). Bovine eNOS was overexpressed in one strain (eNOS TG-Kobe), whereas the human eNOS gene was overexpressed in the other strain (eNOS TG-RT). Non-TG (NTG) and eNOS TG mice were subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion, and the extent of myocardial infarction was determined. Myocardial infarct size was reduced by 33% in the eNOS TG-Kobe strain ( P < 0.05 vs. NTG) and by 32% in the eNOS TG-RT strain ( P < 0.05 vs. NTG). However, postischemic cardiac function (cardiac output, fractional shortening) was not improved in the eNOS TG-Kobe mouse at 24 h of reperfusion [ P = not significant (NS) vs. NTG]. In additional studies, eNOS TG-Kobe mice were subjected to 30 min of myocardial infarction and 7 days of reperfusion. Fractional shortening and the first derivative of left ventricular pressure were measured in eNOS TG-Kobe and NTG mice, and no significant differences in contractility were observed ( P = NS) between the eNOS TG mice and NTG controls. Left ventricular end-diastolic pressure was significantly ( P < 0.05 vs. NTG) reduced in the eNOS TG-Kobe strain at 7 days of reperfusion. The cardioprotective effects of eNOS overexpression on myocardial infarct size were ablated by Nω-nitro-l-arginine methyl ester (300 mg/kg) pretreatment. Thus genetic overexpression of eNOS in mice attenuates myocardial infarction after MI/R but fails to significantly protect against postischemic myocardial contractile dysfunction in mice.

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