scholarly journals Role of ischemic preconditioning in cardioprotective mechanisms of mCRP deposited myocardium in a rat model

2020 ◽  
Author(s):  
Eun Na Kim ◽  
Jae-Sung Choi ◽  
Chong Jai Kim ◽  
So Ra Kim ◽  
Ki-Bong Kim ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Mrna Expression ◽  
Ischemic Preconditioning ◽  
Rat Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Study Groups ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride

AbstractThe deposition of monomeric C-reactive protein (mCRP) in the myocardium aggravates ischemia-reperfusion injury (IRI) and myocardial infarction. Ischemic preconditioning (IPC) is known to protect the myocardium against IRI. We evaluated the effects of IPC on mCRP-deposited myocardium due to IRI in a rat model. Myocardial IRI was produced by ligation of the coronary artery. Direct IPC was applied before IRI using multiple short direct occlusions of the coronary artery. CRP was infused intravenously after IRI. The study groups included the following: sham (n=3), IRI only (n=5), IRI+CRP (n=9), and IPC+IRI+CRP (n=6) groups. The infarct area and area at risk were assessed using Evans blue and 2,3,5-triphenyltetrazolium chloride (2,3,5-TTC) staining. Additionally, mCRP immunostaining and interleukin (IL)-6 mRNA reverse transcriptase-polymerase chain reaction (RT-PCR) were performed. In the IRI+CRP group, the infarcted area, mCRP deposition, and IL-6 mRNA expression were higher than those in the IRI only group. However, in the IPC+IRI+CRP group, the infarction (20% vs. 34% p=0.085) and mCRP myocardial deposition (21% vs. 44%, p=0.026) were lower and IL-6 mRNA expression was higher than those in the IRI+CRP group (fold change, 407 vs. 326, p=0.808), although this was not statistically significant. IPC has cardioprotective effects against myocardial damage caused by mCRP deposition. This protective effect is related to the increase in IL-6 mRNA expression.

Abstract 141: Inhibition of Coagulation Factor Xa Attenuates Myocardial Ischemia Reperfusion Injury in Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Jens Posma ◽  
Jelle Posthuma ◽  
Rene Van Oerle ◽  
Stefan Heitmeier ◽  
Hugo Ten Cate ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coagulation Factor ◽  
Myocardial Damage ◽  
Reperfusion Therapy ◽  
Coagulation Cascade ◽  
Early Model ◽  
Area At Risk ◽  
Protease Activated Receptors ◽  
Tetrazolium Chloride

Background: Ischemic/reperfusion (I/R) injury substantially effects the outcome of myocardial infarction (MI). Current reperfusion therapy does not sufficiently prevent injury caused by microvascular thrombo-inflammation. Coagulation proteases mediate inflammation via protease activated receptors. FXa induced thrombin generation is the key step in the coagulation cascade. We hypothesize that inhibition of FXa by rivaroxaban attenuates I/R injury after MI. Methods: Male WT c57BL/6 mice (age 8-9 weeks, n=8 per group) underwent surgical ligation of the left anterior descending coronary artery 7 days prior to experimentation. Next, the ligature was tightened for 1h to induce ischemia and loosened either at 4h (early), or at 4 weeks (late), to allow reperfusion. The intervention consisted of 2 rivaroxaban (1.6 mg/kg) i.v.-injections or placebo (0.9%NaCl) after 15min of ischemia and 5min of reperfusion. In the early model. the area at risk (AAR) was visualized through Evans blue and differentiated from the area of infarction (AOI) through triphenyl tetrazolium chloride staining. Plasma cardiovascular markers were quantified using Luminex Multiplex. In the late model, LVEF was measured 10min pre-ischemia and 4 weeks’ post-reperfusion utilizing echocardiography. Results: The rivaroxaban treatment group showed signs of diminished myocardial damage as indicated by reduced median AOI/AAR (41%[IQR34-48] vs. control 62%[IQR52-67] p<0.001). This was supported by a better preserved LVEF after 4 weeks of reperfusion (25%[IQR19-31] vs. control (16%[IQR12-21]). Although not significantly different, plasma E-Selectin, PECAM-1, PAI-1, proMMP9, and thrombomodulin showed a trend to increased levels upon treatment with rivaroxaban. Conclusion: FXa inhibition by rivaroxaban significantly reduces myocardial I/R injury in mice and may provide long term preservation of LVEF. Raised cardiovascular markers suggest increased tissue remodeling and phenotypical alteration of endothelial cells after rivaroxaban treatment. These results suggest that coagulation proteases (i.e. FXa) play a relevant role in I/R injury during MI, most likely through activation of protease activated receptors.

scholarly journals Cardioprotective Effect of Novel Matrix Metalloproteinase Inhibitors

2020 ◽  
Vol 21 (19) ◽  
pp. 6990
Author(s):  
Kamilla Gömöri ◽  
Tamara Szabados ◽  
Éva Kenyeres ◽  
Judit Pipis ◽  
Imre Földesi ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Positive Control ◽  
Matrix Metalloproteinase 2 ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride

Background: We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. Methods: Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. Results: MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. Conclusions: This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

scholarly journals Febuxostat Modulates MAPK/NF-κBp65/TNF-α Signaling in Cardiac Ischemia-Reperfusion Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Sana Irfan Khan ◽  
Rajiv Kumar Malhotra ◽  
Neha Rani ◽  
Anil Kumar Sahu ◽  
Ameesha Tomar ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Morphological Alterations ◽  
Treatment Groups ◽  
Antiapoptotic Proteins ◽  
Male Wistar Rats

Xanthine oxidase and xanthine dehydrogenase have been implicated in producing myocardial damage following reperfusion of an occluded coronary artery. We investigated and compared the effect of febuxostat and allopurinol in an experimental model of ischemia-reperfusion (IR) injury with a focus on the signaling pathways involved. Male Wistar rats were orally administered vehicle (CMC) once daily (sham and IR + control), febuxostat (10 mg/kg/day; FEB10 + IR), or allopurinol (100 mg/kg/day; ALL100 + IR) for 14 days. On the 15th day, the IR-control and treatment groups were subjected to one-stage left anterior descending (LAD) coronary artery ligation for 45 minutes followed by a 60-minute reperfusion. Febuxostat and allopurinol pretreatment significantly improved cardiac function and maintained morphological alterations. They also attenuated oxidative stress and apoptosis by suppressing the expression of proapoptotic proteins (Bax and caspase-3), reducing TUNEL-positive cells, and increasing the level of antiapoptotic proteins (Bcl-2). The MAPK-based molecular mechanism revealed suppression of active JNK and p38 proteins concomitant with the rise in ERK1/ERK2, a prosurvival kinase. Additionally, a reduction in the level of inflammatory markers (TNF-α, IL-6, and NF-κB) was also observed. The changes observed with febuxostat were remarkable in comparison with those observed with allopurinol. Febuxostat protects relatively better against IR injury than allopurinol by suppressing inflammation and apoptosis mediating the MAPK/NF-κBp65/TNF-α pathway.

Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice

2006 ◽  
Vol 291 (5) ◽  
pp. H2533-H2540 ◽  
Author(s):  
Tobias Eckle ◽  
Almut Grenz ◽  
David Köhler ◽  
Andreas Redel ◽  
Melanie Falk ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Transgenic Mice ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Troponin I ◽  
Coronary Artery Occlusion ◽  
Systematic Evaluation ◽  
Weight System ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride

Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of transgenic mice seems critical. Due to technical difficulty associated with performing cardiac IP in mice, we developed an in situ model for cardiac IP using a hanging-weight system for coronary artery occlusion. This technique has the major advantage of eliminating the necessity of intermittently occluding the coronary artery with a knotted suture. To systematically evaluate this model, we first demonstrated correlation of ischemia times (10–60 min) with infarct sizes [3.5 ± 1.3 to 42 ± 5.2% area at risk (AAR), Evan’s blue/triphenyltetrazolium chloride staining]. IP (4 × 5 min) and cold ischemia (27°C) reduced infarct size by 69 ± 6.7% and 84 ± 4.2%, respectively ( n = 6, P < 0.01). In contrast, lower numbers of IP cycles did not alter infarct size. However, infarct sizes were distinctively different in mice from different genetic backgrounds. In addition to infarct staining, we tested cardiac troponin I (cTnI) as marker of myocardial infarction in this model. In fact, plasma levels of cTnI were significantly lower in IP-treated mice and closely correlated with infarct sizes ( R2 = 0.8). To demonstrate transcriptional consequences of cardiac IP, we isolated total RNA from the AAR and showed repression of the equilibrative nucleoside transporters 1–4 by IP in this model. Taken together, this study demonstrates highly reproducible infarct sizes and cardiac protection by IP, thus minimizing the variability associated with knot-based coronary occlusion models. Further studies on cardiac IP using transgenic mice may consider this technique.

scholarly journals Preconditioning protects the heart in a prolonged uremic condition

2012 ◽  
Vol 303 (10) ◽  
pp. H1229-H1236 ◽  
Author(s):  
Gabriella F. Kocsis ◽  
Márta Sárközy ◽  
Péter Bencsik ◽  
Márton Pipicz ◽  
Zoltán V. Varga ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Metabolic Diseases ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Area At Risk ◽  
Protein Levels ◽  
Male Wistar Rats

Metabolic diseases such as hyperlipidemia and diabetes attenuate the cardioprotective effect of ischemic preconditioning. In the present study, we examined whether another metabolic disease, prolonged uremia, affects ischemia/reperfusion injury and cardioprotection by ischemic preconditioning. Uremia was induced by partial nephrectomy in male Wistar rats. The development of uremia was verified 29 wk after surgery. Transthoracic echocardiography was performed to monitor cardiac function. At week 30, hearts of nephrectomized and sham-operated rats were isolated and subjected to a 30-min coronary occlusion followed by 120 min reperfusion with or without preceding preconditioning induced by three intermittent cycles of brief ischemia and reperfusion. In nephrectomized rats, plasma uric acid, carbamide, and creatinine as well as urine protein levels were increased as compared with sham-operated controls. Systolic anterior and septal wall thicknesses were increased in nephrectomized rats, suggesting the development of a minimal cardiac hypertrophy. Ejection fraction was decreased and isovolumic relaxation time was shortened in nephrectomized rats demonstrating a mild systolic and diastolic dysfunction. Infarct size was not affected significantly by nephrectomy itself. Ischemic preconditioning significantly decreased infarct size from 24.8 ± 5.2% to 6.6 ± 1.3% in the sham-operated group and also in the uremic group from 35.4 ± 9.5% to 11.9 ± 3.1% of the area at risk. Plasma ANG II and nitrotyrosine were significantly increased in the uremic rats. We conclude that although prolonged experimental uremia leads to severe metabolic changes and the development of a mild myocardial dysfunction, the cardioprotective effect of ischemic preconditioning is still preserved.

Cardiac interstitial bradykinin release during ischemia is enhanced by ischemic preconditioning

2000 ◽  
Vol 279 (1) ◽  
pp. H116-H121 ◽  
Author(s):  
Hui-Lin Pan ◽  
Shao-Rui Chen ◽  
Gloria M. Scicli ◽  
Oscar A. Carretero
Keyword(s):  
Coronary Artery ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Interstitial Fluid ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Period

Ischemic preconditioning is known to protect the myocardium from ischemia-reperfusion injury. We examined the transmural release of bradykinin during myocardial ischemia and the influence of ischemic preconditioning on bradykinin release during subsequent myocardial ischemia. Myocardial ischemia was induced by occlusion of the left anterior descending coronary artery in anesthetized cats. Cardiac microdialysis was performed by implantation and perfusion of dialysis probes in the epicardium and endocardium. In eight animals, bradykinin release was greater in the endocardium than in the epicardium (14.4 ± 2.8 vs. 7.3 ± 1.7 ng/ml, P < 0.05) during 30 min of ischemia. In seven animals subjected to preconditioning, myocardial bradykinin release was potentiated significantly from 2.4 ± 0.6 ng/ml during the control period to 23.1 ± 2.5 ng/ml during 30 min of myocardial ischemia compared with the non-preconditioning group (from 2.7 ± 0.6 to 13.4 ± 1.9 ng/ml, P < 0.05, n = 6). Thus this study provides further evidence that transmural gradients of bradykinin are produced during ischemia. The results also suggest that ischemic preconditioning enhances bradykinin release in the myocardial interstitial fluid during subsequent ischemia, which is likely one of the mechanisms of cardioprotection of ischemic preconditioning.

P4618Lack of CD31 results in microvascular plugging and increased infarction size in an experimental model of myocardial ischemia-reperfusion injury

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
V Syvannarath ◽  
S Di Carlo ◽  
G Even ◽  
B Gachet ◽  
A Nicoletti ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tyrosine Phosphatase ◽  
Constitutive Expression ◽  
Blue Dye ◽  
Macrophage Phenotype ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride ◽  
The Impact

Abstract Background The success of coronary recanalization therapy for the treatment of myocardial infarction can be hampered by microvascular plugging which prevents effective reperfusion of the ischemic tissue. Due to its constitutive expression in platelets, leukocytes, and endothelial cells and its peculiar tyrosine phosphatase cell detaching signaling properties, the trans-homophilic CD31 receptor may be important to modulate platelet and leukocyte aggregation in the microvasculature. Objective To investigate the impact of CD31 genetic deficiency on the infarct size, peri-infarction microvascular plugging and macrophage phenotype in a mouse model of heart ischemia/reperfusion. Methods Cardiac ischemia was induced in WT and CD31 KO mice (n=30, 15 females and 15 males in each group) by surgical ligation of the left anterior descending coronary artery (LAD) for 45 minutes followed by reperfusion for 72 hours. The area at risk (AAR) and necrotic zone (NZ) were assessed using ImageJ software on three consecutive 1 mm thick slices of the left ventricle (LV) by a combination of a blue dye and 2,3,5-triphenyltetrazolium chloride staining. Parallel sets of experiments served to evaluate by both fluorescence microscopy and cytometry the presence of microvascular plugs and leukocyte phenotype in the infarction area as compared to the peri-necrotic myocardium. Results The AAR was similar in WT and CD31 KO mice (41,7±3,5 vs 37±2,9% of LV, NS) whereas the size of myocardial infarction was significantly greater in CD31 KO as compared to WT mice (23,4±2 vs 17,8±1,7% of LV, p<0,05). Immunofluorescent microscopy showed a dramatic increase in microvascular platelets-rich plugs around the infarction in CD31 KO mice (Figure), confirmed by cytometry analysis (9749±573 vs 5976±376 platelet-leukocyte aggregates/mg of tissue, p<0.001). Furthermore, we found that the ratio between M1 and M2 type macrophages in the peri-infarction myocardium was significantly increased in CD31 KO mice (0,7±0.07) as compared to WT mice (0,4±0.06, p<0,01). Conclusions Our data suggest that CD31 is important for reducing the size of necrosis following coronary recanalization procedures by preventing the no-reflow phenomenon due to microvascular plugging and by promoting a reparative phenotype of peri-infarction macrophages. Acknowledgement/Funding Institut Servier - ANRT (CIFRE doctoral grant)

Effects of selective inhibition of cytochrome P-450 ω-hydroxylases and ischemic preconditioning in myocardial protection

2006 ◽  
Vol 290 (2) ◽  
pp. H500-H505 ◽  
Author(s):  
Kasem Nithipatikom ◽  
Michael P. Endsley ◽  
Jeannine M. Moore ◽  
Marilyn A. Isbell ◽  
John R. Falck ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Canine Heart ◽  
Area At Risk ◽  
Cytochrome P 450

Cytochrome P-450 (CYP) ω-hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP ω-hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP ω-hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 ± 1.0% (control), 9.6 ± 1.5% (0.40 mg/kg DDMS), 4.0 ± 2.0% (0.81 mg/kg DDMS), P < 0.01]. In addition, 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 ± 1.3% (0.032 mg/kg 20-HEDE) and 5.9 ± 1.9% (0.064 mg/kg 20-HEDE), P < 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 ± 2.8% (IPC) to 2.5 ± 1.4% (0.81 mg/kg DDMS), P < 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP ω-hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP ω-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.

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