The cardioprotective effect of dual metallopeptidase inhibition: respective roles of endogenous kinins and natriuretic peptides

2005 ◽  
Vol 83 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Marie-Josée Dumoulin ◽  
Albert Adam ◽  
John Burnett ◽  
Denise Heublein ◽  
Nobuharu Yamaguchi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Natriuretic Peptides ◽  
Ace Inhibitor ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cardioprotective Effect ◽  
Protective Effects ◽  
Hoe 140

The objective of the present study was to assess the cardioprotective effect of dual NEP–ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg·kg–1·d–1). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP.Key words: ACE inhibitors, omapatrilat, bradykinin, natriuretic peptide, ischemia, reperfusion.

scholarly journals Possible mechanism of the cardio-renal protective effects of AVE-0991, a non-peptide Mas-receptor agonist, in diabetic rats

2012 ◽  
Vol 13 (3) ◽  
pp. 334-340 ◽  
Author(s):  
Kulwinder Singh ◽  
Kuldeepak Sharma ◽  
Manjeet Singh ◽  
PL Sharma
Keyword(s):  
Blood Pressure ◽  
Receptor Agonist ◽  
Diastolic Pressure ◽  
Left Ventricular Pressure ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Protective Effects ◽  
Mas Receptor ◽  
Arterial Blood

Hypothesis: This study was designed to investigate the cardio-renal protective effect of AVE-0991, a non-peptide Mas-receptor agonist, and A-779, a Mas-receptor antagonist, in diabetic rats. Materials and methods: Wistar rats treated with streptozotocin (50 mg/kg, i.p., once), developed diabetes mellitus after 1 week. After 8 weeks, myocardial functions were assessed by measuring left ventricular developed pressure (LVDP), rate of left ventricular pressure development (d p/d tmax), rate of left ventricular pressure decay (d p/d tmin) and left ventricular end diastolic pressure (LVEDP) on an isolated Langendorff’s heart preparation. Further, mean arterial blood pressure (MABP) was measured by using the tail-cuff method. Assessment of renal functions and lipid profile was carried out using a spectrophotometer. Results: The administration of streptozotocin to rats produced persistent hyperglycaemia, dyslipidaemia and hypertension which consequently produced cardiac and renal dysfunction in 8 weeks. AVE0991 treatment produced cardio-renal protective effects, as evidenced by a significant increase in LVDP, d p/d tmax, d p/d tmin and a significant decrease in LVEDP, BUN, and protein urea. Further, AVE-0991 treatment for the first time has been shown to reduce dyslipidaemia and produced antihyperglycaemic activity in streptozotocin-treated rats. However, MABP and creatinine clearance remained unaffected with AVE-0991 treatment. Conclusions: AVE-0991 produced cardio-renal protection possibly by improving glucose and lipid metabolism in diabetic rats, independent of its blood pressure lowering action.

Abstract 300: Alda-1 Attenuates Acute Ischemia-reperfusion Mediated Cardiac Damage in Aldehyde Dehydrogenase 2 Mutant Diabetic Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Guodong Pan
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Protective Effects ◽  
Diabetic Mice ◽  
Aldehyde Dehydrogenase 2 ◽  
Cardiac Damage ◽  
Western Blots

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in heart, can remove 4-hydroxy-2-nonenal (4-HNE), a toxic by-products of oxidative stress induced by diabetes and ischemia-reperfusion (I/R) injury. A common inactivating mutation of ALDH2 (termed ALDH2*2) was found in 8% of the world’s population, which causes lower ALDH2 activity in mutation carriers. We hypothesized that Alda-1, the only known activator of both ALDH2 and ALDH2*2 mutation, is able to protect heart from I/R injury in diabetic mice with/without ALDH2*2 mutation. Adult male ALDH2*2 mutant and C57B6 wild-type (WT) mice at 3-4 months of age were made hyperglycemic with streptozotocin injection (150 mg/kg. i.p.). Three weeks after injection, Alzet osmotic pumps were implanted subcutaneously to deliver Alda-1 (10 mg/kg) or vehicle. Mice were sacrificed after one day of pump implantation. Hearts were isolated and subjected to 30-minute ischemic followed by 90-minute reperfusion in a Langendorff apparatus. The basal myocardial ALDH2 activity in diabetic ALDH2*2 mutant was significantly lower than in diabetic WT mice (0.50±0.23 vs 0.83±0.08 mmol/min/μg, -39.8%, p<0.05). Alda-1 significantly increased myocardial ALDH2 activity in both ALDH2*2 (1.17±0.38 mmol/min/μg, +134.0%, p<0.05) and WT (1.46±0.40 mmol/min/μg, +75.9%, p<0.05) diabetic mice. Compared with vehicle, Alda-1 significantly improved left ventricular pressure (LVP), and decreased infarcted areas (IA) both in ALDH2*2 (LVP: 4.30±2.03 vs 15.77±8.99 mmHg, +266.7%, p<0.05; IA: 75.17%±9.49 vs 40.46%±7.20, -46.2%, p<0.05) and WT (LVP: 14.22±7.92 vs 21.96±4.32 mmHg, +54.4%, p<0.05; IA: 42.44%±8.60 vs 28.61%±8.55, -32.6%, p<0.05) subjected to I/R injury. Western-blots showed that Alda-1 decreased levels of 4-HNE protein adducts, and increased levels of mitochondrial complex V in both ALDH2*2 and WT mice. Our data suggest that one-day Alda-1 treatment can confer cardio-protective effects against I/R injury in ALDH2*2 diabetic mice possibly accelerating the detoxification of toxic 4-HNE and thereby protecting mitochondria.

Protective effects of ceruloplasmin against electrolysis-induced oxygen free radicals in rat heart

1991 ◽  
Vol 69 (10) ◽  
pp. 1459-1464 ◽  
Author(s):  
Ramez Chamine ◽  
Mircea Alexandru Mateescu ◽  
Stéphane Roger ◽  
Nobuharu Yamaguchi ◽  
Jacques de Champlain ◽  
...  
Keyword(s):  
Free Radicals ◽  
Rat Heart ◽  
Oxygen Free Radicals ◽  
Diastolic Pressure ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Isolated Rat Heart ◽  
Fast Method ◽  
Protective Effects

The potentially injurious effects of oxygen-derived free radicals (OFR) on the myocardium can be prevented in part by pretreatment with OFR scavengers or antioxidants. Since ceruloplasmin (CP) has been shown to possess potent antioxidant activity and scavenge a variety of OFR in vitro, we have undertaken to study its protective effects against myocardial injury induced by OFR. CP was freshly purified by a fast method that minimized proteolytic enzyme degradation. Free radicals were generated by the electrolysis (10 mA DC current for 1 min) of a Krebs–Henseleit solution perfusing an isolated rat heart preparation under constant pressure conditions. CP (0.25 μM) afforded 80 and 63% protection (n = 8, p < 0.05), respectively, against the deleterious effects of electrolysis-induced OFR on left ventricular pressure and coronary flow. The increase in left ventricular end diastolic pressure used here as an index of heart failure did not occur in the presence of 0.25 μM CP. Moreover, CP significantly reduced the increase of norepinephrine washout in the effluent perfusate after electrolysis suggesting a protection against free radical-induced injury to sympathetic nerve endings.Key words: oxygen free radicals, heart, ceruloplasmin, superoxide dismutase, norepinephrine.

Abstract 374: Targeted Deletion of A 2B Adenosine Receptors Attenuates the Protective Effects of Myocardial Postconditioning

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xinglin Tan ◽  
Stephen L Tilley ◽  
Thomas Krahn ◽  
Bunyen Teng ◽  
S. J Mustafa ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Troponin I ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Heart Weight ◽  
Receptor Subtypes ◽  
Protective Effects ◽  
Targeted Deletion ◽  
Beneficial Effects

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (PostCon). To assess the hypothesis that A 2B adenosine receptor (A 2B AR) activation contributes to PostCon-induced protection, global ischemia-reperfusion was performed with and without PostCon or the selective A 2B agonist, BAY 60 – 6583 (BAY), in isolated wild-type (WT) and A 2B AR knockout (A 2B KO) mouse hearts. In WT hearts, PostCon improved post-ischemic recovery of left ventricular developed pressure (LVDP) to 63.3±1.6 % of pre-ischemic baseline vs. 49.9±1.6 % in non-PostCon controls (CTL), lowered end diastolic pressure (EDP) to 15.8±1.5 mmHg vs. 27.9±1.6 mmHg in CTL, and reduced coronary efflux of cardiac troponin I (cTnI) to 2507±359 ng/g heart weight vs. 4693±343 ng/g in CTL (n=12 both groups, p <0.05 each comparison). Treatment with BAY in the first two min of reperfusion mimicked beneficial effects of PostCon in WT hearts (LVDP: 64.7±2.0 % baseline, EDP: 16.2±2.0 mmHg, cTnI: 3311±366; n=13, not significant compared to respective PostCon values). Real-time PCR confirmed absence of A 2B AR in A 2B KO hearts and demonstrated no changes in expression of other adenosine receptor subtypes compared with WT hearts. In A 2B KO hearts, neither PostCon nor BAY improved recovery of LVDP (50.8±1.6 % baseline for CTL vs. 54.5±1.7 % with PostCon vs. 53.0±1.4 with BAY; n=6 each group), and neither affected EDP or release of cTnI. During reperfusion, both PostCon and BAY increased survival kinase signaling through Akt and ERK1/2 phosphorylation in WT but not A 2B KO hearts. In non-ischemic WT hearts, Akt and ERK1/2 phosphorylation was increased by both BAY treatment and application of the PostCon stimulus. These data demonstrate that the protective effects of PostCon are attenuated by targeted deletion of A 2B AR and are mimicked by selective A 2B AR activation, suggesting A 2B AR activation is an important trigger leading to PostCon-induced myocardial protection.

Effects of exercise training on contractile function in myocardial trabeculae after ischemia-reperfusion

2005 ◽  
Vol 99 (1) ◽  
pp. 230-236 ◽  
Author(s):  
Hyosook Hwang ◽  
Peter J. Reiser ◽  
George E. Billman
Keyword(s):  
Exercise Training ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Isometric Force ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Aerobic Exercise Training ◽  
Protective Effects ◽  
Shortening Velocity ◽  
Cross Sectional

Potential protective effects of aerobic exercise training on the myocardium, before an ischemic event, are not completely understood. The purpose of the study was to investigate the effects of exercise training on contractile function after ischemia-reperfusion (Langendorff preparation with 15-min global ischemia/30-min reperfusion). Trabeculae were isolated from the left ventricles of both sedentary control and 10- to 12-wk treadmill exercise-trained rats. The maximal normalized isometric force (force/cross-sectional area; Po/CSA) and shortening velocity ( Vo) in isolated, skinned ventricular trabeculae were measured using the slack test. Ischemia-reperfusion induced significant contractile dysfunction in hearts from both sedentary and trained animals; left ventricular developed pressure (LVDP) and maximal rates of pressure development and relaxation (±dP/d tmax) decreased, whereas end-diastolic pressure (EDP) increased. However, this dysfunction (as expressed as percent change from the last 5 min before ischemia) was attenuated in trained myocardium [LVDP: sedentary −60.8 ± 6.4% (32.0 ± 5.5 mmHg) vs. trained −15.6 ± 8.6% (64.9 ± 6.6 mmHg); +dP/d tmax: sedentary −54.1 ± 4.7% (1,058.7 ± 124.2 mmHg/s) vs. trained −16.7 ± 8.4% (1,931.9 ± 188.3 mmHg/s); −dP/d tmax: sedentary −44.4 ± 2.5% (−829.3 ± 52.0 mmHg/s) vs. trained −17.9 ± 7.2% (−1,341.3 ± 142.8 mmHg/s); EDP: sedentary 539.5 ± 147.6%; (41.3 ± 6.0 mmHg) vs. trained 71.6 ± 30.6%; 11.4 ± 1.2 mmHg]. There was an average 26% increase in Po/CSA in trained trabeculae compared with sedentary controls, and this increase was not affected by ischemia-reperfusion. Ischemia-reperfusion reduced V0 by 39% in both control and trained trabeculae. The relative amount of the β-isoform of myosin heavy chain (MHC-β) was twofold greater in trained trabeculae as well as in the ventricular free walls. Despite a possible increase in the economy in the trained heart, presumed from a greater amount of MHC-β, ischemia-reperfusion reduced Vo, to a similar extent in both control and trained animals. Nevertheless, the trained myocardium appears to have a greater maximum force-generating ability that may, at least partially, compensate for reduced contractile function induced by a brief period of ischemia.

scholarly journals N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1

2008 ◽  
Vol 295 (2) ◽  
pp. H728-H735 ◽  
Author(s):  
Beihua Zhong ◽  
Donna H. Wang
Keyword(s):  
Protective Effect ◽  
Receptor Antagonist ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Mammalian Brain ◽  
Transient Receptor Potential Vanilloid

N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endovanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in gene-targeted TRPV1-null mutant (TRPV1−/−) mice. Hearts of WT or TRPV1−/− mice were Langendorffly perfused with OLDA (2 × 10−9 M) in the presence or absence of CGRP8–37 (1 × 10−6 M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 × 10−6 M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 × 10−6 M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 × 10−4 M), a nonselective K+ channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/d t (+dP/d t) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not TRPV1−/− hearts by increasing LVDP, CF, and +dP/d t and by decreasing LVEDP. CGRP8–37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioimmunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in TRPV1−/− hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or K+ channel antagonists. The protective effect of OLDA is void in TRPV1−/− hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury.

scholarly journals Lack of the effect of superoxide dismutase and catalase on Na+,K+-ATPase activity in stunned rabbit hearts

2008 ◽  
pp. S61-S66
Author(s):  
P Kaplán ◽  
M Matejovičová ◽  
P Herijgers ◽  
W Flameng
Keyword(s):  
Superoxide Dismutase ◽  
Antioxidant Enzymes ◽  
Atpase Activity ◽  
Cardiac Dysfunction ◽  
Myocardial Stunning ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Significant Loss ◽  
Protective Effects

Reactive oxygen species (ROS) have been implicated in the mechanism of postischemic contractile dysfunction, known as myocardial stunning. In this study, we examined protective effects of antioxidant enzymes, superoxide dismutase (SOD) and catalase, against ischemia/reperfusion-induced cardiac dysfunction and inhibition of Na+,K+-ATPase activity. Isolated Langendorff-perfused rabbit hearts were subjected to 15 min of global normothermic ischemia followed by 10 min reperfusion. The hearts treated with SOD plus catalase did not show significant recovery of left ventricular (LV) end-diastolic pressure compared with untreated ischemic reperfused hearts. Treatment with antioxidants had no protective effects on developed LV pressure or its maximal positive and negative first derivatives (+/-LVdP/dt). Myocardial stunning was accompanied by significant loss in sarcolemmal Na+,K+-ATPase activity and thiol group content. Inhibition of enzyme activity and oxidation of SH groups were not prevented by antioxidant enzymes. These results suggest that administration of SOD and catalase in perfusate do not protect significantly against cardiac dysfunction in stunned rabbit myocardium.

Activation of NF-κB is a critical element in the antiapoptotic effect of anesthetic preconditioning

2009 ◽  
Vol 296 (5) ◽  
pp. H1296-H1304 ◽  
Author(s):  
Xiyuan Lu ◽  
Hong Liu ◽  
Lianguo Wang ◽  
Saul Schaefer
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Reversible Inhibitor ◽  
Critical Element ◽  
Protective Effects ◽  
Anesthetic Preconditioning

Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-κB during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-κB activation before I/R is unknown. Therefore, these experiments tested the hypothesis that APC-induced ROS results in activation of NF-κB before I/R, with consequent increased expression of antiapoptotic proteins such as Bcl-2 and decreased apoptosis. Experiments utilized an established perfused heart rat model of sevoflurane APC and I/R. The role of NF-κB was defined by a novel method of transient inhibition of the regulatory kinase IKK using the reversible inhibitor SC-514. In addition to functional measures of left ventricular developed and end-diastolic pressure, phosphorylation of IκBα and activation of NF-κB were measured along with cytosolic protein content of Bcl-2, release of cytochrome c, and degradation of caspase-3. APC resulted in ROS-dependent phosphorylation of IκBα and activation of NF-κB before I/R. APC also increased the expression of Bcl-2 before I/R. In addition to functional protection following I/R, APC resulted in lower release of cytochrome c and caspase-3 degradation. These protective effects of APC were abolished by transient inhibition of IκBα phosphorylation and NF-κB activation by SC-514 followed by washout. ROS-dependent activation of NF-κB by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-κB activation before I/R should protect hearts from I/R injury.

scholarly journals Inhibition of Na+/Ca2+ exchange by KB-R7943: transport mode selectivity and antiarrhythmic consequences

2001 ◽  
Vol 281 (3) ◽  
pp. H1334-H1345 ◽  
Author(s):  
Chadwick L. Elias ◽  
Anton Lukas ◽  
Sabin Shurraw ◽  
Jason Scott ◽  
Alexander Omelchenko ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Xenopus Laevis Oocytes ◽  
Protective Effects ◽  
Patch Clamp Technique ◽  
Reverse Mode ◽  
Intracellular Ca

The Na+/Ca2+ exchanger plays a prominent role in regulating intracellular Ca2+ levels in cardiac myocytes and can serve as both a Ca2+ influx and efflux pathway. A novel inhibitor, KB-R7943, has been reported to selectively inhibit the reverse mode (i.e. , Ca2+ entry) of Na+/Ca2+ exchange transport, although many aspects of its inhibitory properties remain controversial. We evaluated the inhibitory effects of KB-R7943 on Na+/Ca2+exchange currents using the giant excised patch-clamp technique. Membrane patches were obtained from Xenopus laevis oocytes expressing the cloned cardiac Na+/Ca2+exchanger NCX1.1, and outward, inward, and combined inward-outward currents were studied. KB-R7943 preferentially inhibited outward (i.e., reverse) Na+/Ca2+ exchange currents. The inhibitory mechanism consists of direct effects on the transport machinery of the exchanger, with additional influences on ionic regulatory properties. Competitive interactions between KB-R7943 and the transported ions were not observed. The antiarrhythmic effects of KB-R7943 were then evaluated in an ischemia-reperfusion model of cardiac injury in Langendorff-perfused whole rabbit hearts using electrocardiography and measurements of left ventricular pressure. When 3 μM KB-R7943 was applied for 10 min before a 30-min global ischemic period, ventricular arrhythmias (tachycardia and fibrillation) associated with both ischemia and reperfusion were almost completely suppressed. The observed electrophysiological profile of KB-R7943 and its protective effects on ischemia-reperfusion-induced ventricular arrhythmias support the notion of a prominent role of Ca2+ entry via reverse Na+/Ca2+ exchange in this process.

scholarly journals Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Raffaella Mastrocola ◽  
Claudia Penna ◽  
Francesca Tullio ◽  
Saveria Femminò ◽  
Debora Nigro ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Protective Effects ◽  
Risk Pathway ◽  
Lactate Dehydrogenase Release ◽  
Pyrin Domain

Although the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome has been recently detected in the heart, its role in cardiac ischemia/reperfusion (IR) is still controversial. Here, we investigate whether a pharmacological modulation of NLRP3 inflammasome exerted protective effects in an ex vivo model of IR injury. Isolated hearts from male Wistar rats (5-6 months old) underwent ischemia (30 min) followed by reperfusion (20 or 60 min) with and without pretreatment with the recently synthetized NLRP3 inflammasome inhibitor INF4E (50 μM, 20 min before ischemia). INF4E exerted protection against myocardial IR, shown by a significant reduction in infarct size and lactate dehydrogenase release and improvement in postischemic left ventricular pressure. The formation of the NLRP3 inflammasome complex was induced by myocardial IR and attenuated by INF4E in a time-dependent way. Interestingly, the hearts of the INF4E-pretreated animals displayed a marked improvement of the protective RISK pathway and this effect was associated increase in expression of markers of mitochondrial oxidative phosphorylation. Our results demonstrate for the first time that INF4E protected against the IR-induced myocardial injury and dysfunction, by a mechanism that involves inhibition of the NLRP3 inflammasome, resulting in the activation of the prosurvival RISK pathway and improvement in mitochondrial function.

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