Quercetin is a Potential Therapy for Postinfarction Netosis Formation

doi:10.21203/rs.3.rs-5145642/v1

Download PDF

Research Article

Quercetin is a Potential Therapy for Postinfarction Netosis Formation

https://doi.org/10.21203/rs.3.rs-5145642/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Purpose. The surgical intervention during myocardial infarction (MI) is associated with the risk of reperfusion injury, infiltration of tissues with polymorphonuclear neutrophils and neutrophil extracellular traps (NETs) formation. We hypothesized that inhibition of NETs with the use of quercetin might be a promising cardioprotective strategy.

Methods. Wistar rats underwent LAD occlusion (MI) for 40 min followed by 90 min of reperfusion. MI+Q group received a water-soluble form of Quercetin (50 mg/kg, “Corvitin”, BCPP, Ukraine) into the tail vein 10 min before reperfusion.

Results. The post-MI administration of Quercetin significantly alleviated cardiac dysfunction. End-systolic pressure; stroke volume; cardiac output; and stroke work were significantly improved in MI+Q vs MI group. NETs formation (examined by fluorescence microscopy and Hoechst staining) as well as free DNA in blood plasma was reduced in MI+Q group that might be one of the mechanisms of cardioprotective effect of quercetin.

Conclusions. Postconditioning with Quercetin might be used as a therapeutic tool for alleviation of reperfusion injury and netosis inhibition in vivo.

netosis

heart

ischemia

reperfusion

myocardial infarction

quercetin

The formation of neutrophil extracellular traps (NETs) is one of the non-specific mechanisms of the organisms’ innate defense. This is a unique property of granulocytic polymorphonuclear cells (PMNs). The role of this phenomenon is not limited to the infectious process only. In recent years, NETs formation was also described as a factor in the pathogenesis of so-called “sterile” inflammation, which is an important mechanism of many disorders. In particular, the recent studies showed the significance of NETs in the autoimmune disorders, thrombosis, and pathogenesis of tumor (Corsiero et al. 2016; Döring et al. 2017) as well as in the ischemia-reperfusion of limbs, liver, kidneys, and lungs (Oklu et al. 2013; Huang et al. 2015; Raup-Konsavage et al. 2018).

Myocardial infarction (MI) is the leading cause of mortality worldwide. The most effective therapeutic approach for MI is an early surgical intervention aimed to renew blood supply of the ischemized zone of myocardium. Despite of the time, any surgical manipulation is associated with a high risk of reperfusion injury. PMNs infiltrate myocardial tissues during the early reperfusion period increasing the infarct area due to the release of reactive oxygen species and proteolytic enzymes that are the main contributors to the secondary alteration and inflammation progression. Barrett et al. showed that perfusion of the isolated heart with the solution containing PMNs significantly increased ischemic-reperfusion injury and the blockade of the cell adhesion molecules abolished this effect (Barrett et al. 1993). In the work of de Boer et al., the presence of NETs in the coronary thrombosis of the patients with myocardial infarction was shown by the histone H1, myeloperoxidase, and neutrophil elastase colocalization (de Boer et al. 2013). On the other hand, PMNs accumulated in the myocardium during the reperfusion can digest the necrotic tissues as well as produce a significant number of interleukins and, thus, play an important role in the infarct healing (Horckmans et al. 2017). This evidence allows us to suggest the importance of the NETs in the pathogenesis of MI.

An exceptionally positive effect of bioflavonoid Quercetin (3,3′,4′,5,7-pentahydroxyflavone) has been demonstrated in many experimental models of cardiovascular system damage. Quercetin possesses powerful antioxidant and anti-inflammatory effects as well as antiradical properties scavenging reactive oxygen species (superoxide anion, singlet oxygen) and attenuating lipid peroxydation (Morales et al. 2012; Ertuğ et al. 2013). Quercetin also can act as an inhibitor of both protein kinase C and proteasome (Pashevin et al. 2011; Chen et al. 2005) – the key enzymes in the NETs formation process (Lapponi et al. 2013). Previously we showed that application of the specific proteasomal inhibitor diminished NETs formation and prevented the death of cardiomyocytes in coculture with activated neutrophils during anoxia-reoxygenation, thus, preventing the secondary alteration of isolated cardiomyocytes (Pashevin et al.2015). In this study, we test the hypothesis that treatment with Quercetin might inhibit NETs formation and improve heart function in in vivo model of acute MI. We demonstrated that intravenous administration of water-soluble Quercetin before reperfusion significantly improved cardiac function restoration, significantly decreased NETs formation and content of free DNA concentration in blood plasma. Thus, the inhibition of netosis might be new a therapeutic/cardioprotective mechanism of Quercetin.

2.1 Solutions and Drugs. We used the water-soluble form of Quercetin “Corvitin” (PJSC SIC “Borshchahivskiy CPP”, Kyiv, Ukraine). RPMI medium, fetal bovine serum (FBS), antibiotics, Hoechst 33342, phorbol myristate acetate (PMA), Percoll, Hanks balanced salt solution (HBSS), glucose, and salts were purchased from Sigma Chemical (USA). Free DNA concentration was measured using the Quant-iTPicoGreen dsDNA assay kit (Invitrogen).

2.2 Animals and bioethics. All of the manipulations with laboratory animals were performed in accordance with the guidelines of the Declaration of Helsinki, Directive 2010/63/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes (22.09.2010) and Document №3447-IV (2006) of the Parliament of Ukraine “On the Protection of Animals from Brutal Treatment”. The protocol of the study was approved by the Institutional Committee on Bioethics.

Thirty-two male Wistar rats, 330–350 g of weight, were housed in standard conditions and kept on a 12 h light/dark cycle with ad libitum access to food and water. Animals were randomized into three groups: sham-operated (n = 10), MI group (n = 11), and MI + Quercetin (MI + Q) group (n = 11).

2.3. In vivo model of MI and cardiodynamics assay. MI was induced by ligation of the left anterior descending coronary artery (LAD). Briefly, rats were anesthetized with 1,5 g/kg of urethane and fixed at the surgery table. When the adequacy of anesthesia was monitored by loss of muscular tone, the trachea was catheterized and connected to a small animal lung ventilation apparatus (Harvard apparatus, USA). The right carotid artery was separated and catheterized with the ultrathin catheter (2F) with the Pressure-Volume sensor (Millar Instruments, USA). The catheter was moved further to the left ventricle of the heart to obtain a clear P-V loop at a monitor. After 15–20 min of steady state, the cut between the fifth and the sixth ribs was performed, and an extender was placed to get access to the heart. Then, the LAD artery was ligated with a 5 − 0 propylene suture (3/8, 6/0, 10 mm, Medicor-Budapest) for 40 min. Reperfusion was initiated by removing the ligature from the LAD. Next, recording of cardiodynamic parmeters was continued for the following 90 min.

In the sham-operated group, the procedure was stopped after the ligature was undergone below the LAD artery without making a nod. In the MI + Q group, Quercetin was injected 10 min before the start of reperfusion at the dose of 50 mg/kg into the tail vein.

Digital signal from 2F as P-V loop was recorded with data acquisition system throughout the experiment in online mode and later analyzed with PVan-400 software. The following cardiodynamic parameters were assessed: end-diastolic pressure (EDP), end-systolic pressure (ESP), +dP/dt_max and -dP/dt_max, end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), the heart rate, cardiac output (CO), and stroke work (SW). Data were analyzed starting from baseline values, at the 5th and the 40th min after LAD artery ligation, and at the 5th, 30th, 60th and 90th min of reperfusion.

2.4. PMNs isolation and NETs detection. In order to obtain PMNs, the blood of animals was collected and stabilized by EDTA in monovettes (Sarstedt), mixed with 0.9% NaCl in a ratio of 1:1, and carefully laminated on the Percoll gradient with layer densities of 45%, 54%, and 63%. After gradient centrifugation of the blood (3,000 rpm for 15 min), PMNs were detected between the second and third layers. The granulocytes were then washed with HBSS buffer and diluted in RPMI media with 10% (v/v) of heat inactivated FBS. The PMNs were plated in the 24-well dish or in the cell culture Petri dish with a density of 100 000 cells/cm². To stimulate NETs formation as a positive control, 20 nM of PMA were added to cell cultures for 3 h. Detection of NETs was performed using a fluorescence microscope with the staining of cells with fluorogenic dyes Hoechst 33342 (biz-benzamide) and propidium iodide that directly stain chromatin (3.75 mM).

Additionally, the concentration of DNA released into the blood stream was measured in blood plasma using Hitachi 4000 spectrophotometer with a Quant-iTPicoGreen dsDNA assay kit (Invitrogen) following the manufacturer’s instruction.

2.5. Statistics

Shapiro-Wilk test was used to evaluate the normality of the distribution of data in each group. Levine’s test was used to detect the homogeneity of variance among groups. In the case of homogeneity, a one-way analysis of variance (ANOVA) was applied to compare means between homogeneous groups followed by the Bonferroni post hoc test. While comparing heterogeneous or not normally distributed data, the Kruskal-Wallis test with Mann-Whitney post hoc analysis was adopted. P < 0.05 was assumed as statistically significant.

3.1. Effect of quercetin on the cardiodynamic in MI model

Analysis of cardiodynamic parameters at baseline showed no significant differences between groups (Table 1). Although the average meaning of + dP/dt_max was lower in the MI group than in the sham-operated group, the mean value of ESP did not differ significantly. Other parameters showed no statistical differences and were about similar meaning in all groups indicating homogeneity of animals chosen for the study. For further analysis of cardiodynamic parameters changes at reperfusion, the base point values were assumed as 100% and all data were converted to percentages. A comparative analysis was performed between three groups in each time point.

Table 1

Base values of cardiodynamics of groups included into the study
Parameter	Sham-operated (n = 10)	MI (n = 11)	MI + Quercetin (n = 11)
Heart Rate (beats per min)	341.5 ± 14.0	349.4 ± 13.0	354.4 ± 6.4
End-Systolic Pressure (mmHg)	129.4 ± 10.5	112.0 ± 7.0	123.2 ± 11.0
End-Diastolic Pressure (mmHg)	5.0 ± 0.8	7.1 ± 1.1	8.4 ± 1.8
+dP/dt _max (mmHg/sec)	16002 ± 997	12216 ± 1054*	15334 ± 1296
-dP/dt _max (mmHg/sec)	6855 ± 561	6193 ± 391	7187 ± 469
End-Systolic Volume (µl)	157.1 ± 20.4	162.6 ± 27.1	205.3 ± 18.7
End-Diastolic Volume (µl)	312.1 ± 21.6	315.1 ± 33.4	359.0 ± 53.0
Stroke volume (µl)	157.4 ± 25.2	144.4 ± 12.7	150.1 ± 23.5
Stroke work (mmHg*µl)	18067 ± 3097	14336 ± 1564	18521 ± 3455
Cardiac output (µl per min)	52681 ± 8958	50058 ± 5526	53738 ± 8989
Ejection fraction (%)	57.8 ± 3.4	53.0 ± 5.8	51.0 ± 4.4
P < 0.05 compared to sham-operated as calculated by one-way ANOVA followed by the Bonferroni post hoc* test.

In the MI group, LAD ligation and subsequent reperfusion significantly affected heart function. At the 90th min of reperfusion, ESP was 66.6 ± 7.1% from the base line point that was significantly lower (P < 0.05) comparing to sham-operatedratswho showed only 89 ± 5.8% of ESP (Fig. 1A).Contractile activity as detected by + dP/dt_max decreased significantly from the 30th min of reperfusion in the MI group when compared to the sham-operated group (Fig. 1C). Although EDP was not changed till the end of observation (Fig. 1B), -dP/dt_max decreased significantly starting from the 5th min of reperfusion in the MI group (Fig. 1D) that indicates impairment of relaxation process. Similarly, LAD occlusion and reperfusion induced changes in pump function of the heart: significant decrease inEDV (Fig. 1E), ESV (Fig. 1F), SV (Fig. 1G), and CO (Fig. 1J) were observed.This data shows a drastic decrease in cardiac performance in rats with acute MI modeling.

Intravenous injection of Quercetin 10 min before reperfusion prevented reperfusion disturbances of the heart function. At the 90th min of reperfusion, ESP averaged 107.5% in animals of the MI + Q group vs 66.6% in the MI group (P < 0.05). Despite non-significant changes in ejection fraction (Fig. 1I), at the 90th minute of reperfusion EDV was 92.6 ± 15% from the initial value which was 40.9% higher than in the MI group (51.7 ± 9.8%, P < 0.05). At the same time point, the values of SV, CO, and SW were 46%, 39%, and 40% higher in the MI + Q group compared to the MI group (P < 0.05 for all) (Fig. 1G, J, K). Notably, the difference in volume parameters was significant since the 30th minute of reperfusion. Thus, our data indicate that Quercetin post-treatment provides a cardioprotective effect alleviating negative effect of reperfusion and preserving the contractile and pumping function of the myocardium.

3.2 Analysis of NETs formation in PMNs after MI modeling with and without Quercetin treatment.

We found an increase of NETs formation by PMNsisolated from blood ofratsofMI group.It was evaluated by direct calculation of isolated PMNs and by measurement of free DNA level in the plasma of the same animals. The amount of spontaneously formed NETs after MI modeling was 2,3 times higher (P < 0,05) than in the sham-operated group. Administration of Quercetin before the reperfusion decreased the amount of spontaneously formed NETs to 4,3 ± 1,4% which was 1,9 times less (P < 0,05) than in the MI group and only 1,3 times higher (P < 0,05) than in the sham-operated animals (Fig. 2A). Additional stimulation of isolated PMNs with PMA increased the number of formed NETs in all three groups. Thus, it was the highest in the group with MI modeling (17,7 ± 7,1%). In the sham-operated group, this number was estimated as 11,5 ± 5,8%, and Quercetin treatment led to the decrease of induced NETs formation by 1,5 times (Fig. 2B).

Notably, some amount of PMNs with incomplete NETs was detected in these experiments. Neutrophils with unorganized (unfinished) NETs had round-shaped, big nuclei without signs of chromatin condensation or fragmentation. The nuclei of these cells were not stained by propidium iodidum meaning that the integrity of PMNs membranes remains intact (Fig. 2C, 2D, 2E). Such a phenomenon has also been described previously (Yost et al. 2009). The number of such cells was not significantly decreased during MI modeling and was restored to the level of the sham-operated group by treatment with Quercetin. This is still an important point because these changes indicate that during MI an increase in NETs percentages occurred not only because of the significant decrease in the general number of living cells but also becausenot all PMNs have finished the formation of NETs. PMA stimulation revealed the same tendency: the amount of PMNs with signs of uncompleted NETs formation was 4,4% in the sham group, 4,1% in the MI group and 2,8% in the MI + Q group.

These findings are supported by free DNA measurement in the blood plasma. The level of free DNA in the blood plasma of rats with MI modeling was 2,3 times higher than in the sham-operated group (6,8 ng/ml vs 2,93 ng/ml correspondingly, P < 0,05). Quercetin administration before reperfusion decreased this level to 4,7 ng/ml (1,4 times less than in the MI group, P < 0,05).

The development of an effective therapeutic approach for surgical intervention in MI patience is still an urgent task for biomedical researchers. These pharmacologic agents should possess high biocompatibility properties, low toxicity and multitarget mechanisms of action to overcome the damaging effect of ischemia-reperfusion. Quercetin is a polyphenolic natural compound and has been extensively studied as an antioxidant, anti-inflammatory and cardioprotective agent in recent decades.

The present study was designed to establish the effect of water-soluble Quercetin administration in in vivo model of acute MI with the focus on NETs formation. The main finding of this work is that water-soluble Quercetin administration during MI modeling improved contractile and pump function of the heart at reperfusion and prevented NETs formation.

Here, we showed that one of the cardioprotective mechanisms of Quercetin is the inhibition of NETs formation in the acute MI model in vivo. Previously we have demonstrated that preincubation with Quercetin significantly decreased PMA-induced NETs formation in isolated PMN neutrophils (Pashevin et al. 2015). This effect occurred due to inhibition of proteasome activity which is an extremely important regulator of cellular functions including NETs formation.

Quercetin reveals different mechanisms of action that are important during MI and post-infarction pathways of inflammation. Quercetin can attenuate oxidative stress decreasing expression of NADPH oxidasegene, stimulating expression of superoxide dismutase 1, glutathione peroxidase, and catalase genes (Kobori et al. 2016). Quercetin can inhibit activity of lipoxygenase (Kim et al. 1998) that cleaves phospholipids with formation of leukotrienes and other proinflammatory mediators. There are also data about ability of quercetin to decrease cytotoxic effects of ischemia-reperfusion, hydrogen peroxide, doxorubicin, etc (Bartekova et al. 2016; Kocahan et al. 2017). Thus, this bioflavonoid is extremely important for the therapy of MI and pharmacological regulation of different types of programmed cell death including apoptosis, autophagy, and closely related to these mechanisms of NETs program progression. Our results showed that the water-soluble form of Quercetin significantly decreased the number of formed NETs in in vivo model of acute MI modeling. This, in turn, leads to less pronounced disturbances of heart function at reperfusion.

Nowadays, it becomes clearer that NETs formation is involved in negative consequences of MI (Ge et al. 2015). Our data are in agreement with the results of Yuan et al., who showed that Quercetin inhibited neutrophil infiltration and reduced the plasma levels of inflammatory cytokines rheumatoid arthritis (Yuan et al. 2020). The necessity of NETs prevention during heart ischemia is also supported by the data concerning the role of NETs in blocking reperfusion (re-flow) in small coronary vessels during cardiac surgery manipulation (Ge et al. 2015). Moreover, reactive oxygen species during ischemia-reperfusion can activate NETs formation leading to a more pronounced reperfusion injury (Kocahan et al. 2017; Al-Khafaji et al. 2016). All this data indicates that NETs play a pathological role during MI. Some authors have even investigated whether circulating NETs-related components are associated with clinical outcome and hypercoagulability in ST-elevation myocardial infarction (Langseth et al. 2020).

There are some reports about the therapeutic influence on NETs realization during ischemia-reperfusion injury of internal organs. Japanese researchers influenced the thrombogenic action of PMN with thrombomodulin (Shrestha et al. 2019; Hayase et al. 2020). Other authors have demonstrated the protective effects of DNAse-1 treatment in a rat model of intestinal ischemia-reperfusion (Wang et al. 2018). These drugs did not demonstrate other cardioprotective properties, are expensive, and have severe side effects. The same problem exists with selective proteasomal inhibitors such as clasto-lactacystin beta-lactone, MG-132 or bortezomib, the drug introduced in the clinical practice. On the contrary, the water-soluble form of Quercetin has a wide-range of tissue protective effects, improving the post-ischemic heart function restoration and demonstrating the ability to inhibit MI-induced NETs formation that can be used for diminishing the consequences of reperfusion injury in surgical practice and acute ischemic stroke treatment.

Funding statement

This work was supported by Bogomoletz Institute of Physiology, National Academy of science of Ukraine.

Conflicts of interest statement

The authors have no relevant financial or non-financial interests to disclose.

The authors declare that all data were generated in-house and that no paper mill was used.

Author contribution statement

DV and PD conceived and designed research. GY, PD, GS, L-BT, NV and TL conducted experiments. PG and LO contributed analytical tools. GY and PD analyzed data. GY and NV wrote the initial manuscript. All authors read and approved the manuscript.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Bogomoletz Institute of Physiology.

Data Availability statement

All data generated or analysed during this study are included in this published article.

Corsiero E, Pratesi F, Prediletto E, Bombardieri M, Migliorini P (2016) NETosis as Source of Autoantigens in Rheumatoid Arthritis. Front Immunol 7:485. 10.3389/fimmu.2016.00485PMID: 27895639; PMCID: PMC5108063
Döring Y, Soehnlein O, Weber C (2017) Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis. Circ Res. ;120(4):736–743. 10.1161/CIRCRESAHA.116.309692. PMID: 28209798
Oklu R, Albadawi H, Jones JE, Yoo HJ, Watkins MT (2013) Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps. J Vasc Surg 58(6):1627–1636. 10.1016/j.jvs.2013.02.241Epub 2013 May 14. PMID: 23683381; PMCID: PMC3825746
Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, Wang S, Kim J, Billiar T, Wang Y, Tsung A (2015) Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62(2):600–614 Epub 2015 May 29. PMID: 25855125; PMCID: PMC4515210
Raup-Konsavage WM, Wang Y, Wang WW, Feliers D, Ruan H, Reeves WB (2018) Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury. Kidney Int 93(2):365–374. 10.1016/j.kint.2017.08.014Epub 2017 Oct 20. PMID: 29061334; PMCID: PMC5794573
Barrett JA, Derian CK, Swillo RS, Woltmann RF, Perrone MH (1993) The role of the neutrophil and formed elements of the blood in an in vitro model of reperfusion injury. Mediators Inflamm 2(1):85–92 PMID: 18475508; PMCID: PMC2365378
de Boer OJ, Li X, Teeling P, Mackaay C, Ploegmakers HJ, van der Loos CM, Daemen MJ, de Winter RJ, van der Wal AC (2013) Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb Haemost 109(2):290–297. 10.1160/TH12-06-0425Epub 2012 Dec 13. PMID: 23238559
Horckmans M, Ring L, Duchene J, Santovito D, Schloss MJ, Drechsler M, Weber C, Soehnlein O, Steffens S (2017) Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J. ;38(3):187–197. 10.1093/eurheartj/ehw002. PMID: 28158426
Morales J, Günther G, Zanocco AL, Lemp E (2012) Singlet oxygen reactions with flavonoids. A theoretical-experimental study. PLoS ONE 7(7):e40548. 10.1371/journal.pone.0040548Epub 2012 Jul 10. PMID: 22802966; PMCID: PMC3393665
Ertuğ PU, Aydinoglu F, Goruroglu Ozturk O, Singirik E, Ögülener N (2013) Comparative study of the quercetin, ascorbic acid, glutathione and superoxide dismutase for nitric oxide protecting effects in mouse gastric fundus. Eur J Pharmacol 698(1–3):379–387. 10.1016/j.ejphar.2012.10.009Epub 2012 Oct 17. PMID: 23085029
Pashevin DA, Tumanovska LV, Dosenko VE, Nagibin VS, Gurianova VL, Moibenko AA (2011) Antiatherogenic effect of quercetin is mediated by proteasome inhibition in the aorta and circulating leukocytes. Pharmacol Rep. ;63(4):1009-18. 10.1016/s1734-1140(11)70617-x. PMID: 22001989
Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP (2005) Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol. ;69(10):1421-32. 10.1016/j.bcp.2005.02.022. PMID: 15857606
Lapponi MJ, Carestia A, Landoni VI, Rivadeneyra L, Etulain J, Negrotto S, Pozner RG, Schattner M (2013) Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. J Pharmacol Exp Ther 345(3):430–437. 10.1124/jpet.112.202879Epub 2013 Mar 27. PMID: 23536315
Pashevin DO, Nagibin VS, Tumanovska LV, Moibenko AA, Dosenko VE (2015) Proteasome Inhibition Diminishes the Formation of Neutrophil Extracellular Traps and Prevents the Death of Cardiomyocytes in Coculture with Activated Neutrophils during Anoxia-Reoxygenation. Pathobiology 82(6):290–298. 10.1159/000440982Epub 2015 Nov 12. PMID: 26558384
Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, Rodesch CK, Albertine KH, Petti CA, Weyrich AS, Zimmerman GA (2009) Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood 113(25):6419–6427. 10.1182/blood-2008-07-171629Epub 2009 Feb 12. PMID: 19221037; PMCID: PMC2710935
Kobori M, Takahashi Y, Sakurai M, Akimoto Y, Tsushida T, Oike H, Ippoushi K (2016) Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice. Mol Nutr Food Res 60(2):300–312. 10.1002/mnfr.201500595Epub 2015 Nov 24. PMID: 26499876; PMCID: PMC5063128
Kim HP, Mani I, Iversen L, Ziboh VA (1998) Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostaglandins Leukot Essent Fatty Acids. ;58(1):17–24. 10.1016/s0952-3278(98)90125-9. PMID: 9482162
Bartekova M, Radosinska J, Pancza D, Barancik M, Ravingerova T (2016) Cardioprotective effects of quercetin against ischemia-reperfusion injury are age-dependent. Physiol Res. ;65 Suppl 1:S101-7. 10.33549/physiolres.933390. PMID: 27643931
Kocahan S, Dogan Z, Erdemli E, Taskin E (2017) Protective Effect of Quercetin Against Oxidative Stress-induced Toxicity Associated With Doxorubicin and Cyclophosphamide in Rat Kidney and Liver Tissue. Iran J Kidney Dis 11(2):124–131 PMID: 28270644
Ge L, Zhou X, Ji WJ, Lu RY, Zhang Y, Zhang YD, Ma YQ, Zhao JH, Li YM (2015) Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol 308(5):H500–H509. 10.1152/ajpheart.00381.2014Epub 2014 Dec 19. PMID: 25527775
Yuan K, Zhu Q, Lu Q, Jiang H, Zhu M, Li X, Huang G, Xu A (2020) Quercetin alleviates rheumatoid arthritis by inhibiting neutrophil inflammatory activities. J Nutr Biochem 84:108454. 10.1016/j.jnutbio.2020.108454Epub 2020 Jun 20. PMID: 32679549
Al-Khafaji AB, Tohme S, Yazdani HO, Miller D, Huang H, Tsung A (2016) Superoxide induces Neutrophil Extracellular Trap Formation in a TLR-4 and NOX-dependent mechanism. Mol Med 22:621–631. 10.2119/molmed.2016.00054Epub 2016 Jul 18. PMID: 27453505; PMCID: PMC5082303
Langseth MS, Helseth R, Ritschel V, Hansen CH, Andersen GØ, Eritsland J, Halvorsen S, Fagerland MW, Solheim S, Arnesen H, Seljeflot I, Opstad TB (2020) Double-Stranded DNA and NETs Components in Relation to Clinical Outcome After ST-Elevation Myocardial Infarction. Sci Rep 10(1):5007. 10.1038/s41598-020-61971-7PMID: 32193509; PMCID: PMC7081350
Shrestha B, Ito T, Kakuuchi M, Totoki T, Nagasato T, Yamamoto M, Maruyama I (2019) Recombinant Thrombomodulin Suppresses Histone-Induced Neutrophil Extracellular Trap Formation. Front Immunol 10:2535. 10.3389/fimmu.2019.02535PMID: 31736962; PMCID: PMC6828967
Hayase N, Doi K, Hiruma T, Matsuura R, Hamasaki Y, Noiri E, Nangaku M, Morimura N (2020) Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury. Sci Rep 10(1):289. 10.1038/s41598-019-57205-0PMID: 31937858; PMCID: PMC6959219
Wang S, Xie T, Sun S, Wang K, Liu B, Wu X, Ding W (2018) DNase-1 Treatment Exerts Protective Effects in a Rat Model of Intestinal Ischemia-Reperfusion Injury. Sci Rep 8(1):17788. 10.1038/s41598-018-36198-2PMID: 30542063; PMCID: PMC6290768

No competing interests reported.

Download PDF

Editorial decision: Revision requested
17 Oct, 2024
Reviews received at journal
09 Oct, 2024
Reviewers agreed at journal
30 Sep, 2024
Reviewers agreed at journal
27 Sep, 2024
Reviewers invited by journal
27 Sep, 2024
Editor assigned by journal
25 Sep, 2024
Submission checks completed at journal
25 Sep, 2024
First submitted to journal
24 Sep, 2024

You are reading this latest preprint version

Quercetin is a Potential Therapy for Postinfarction Netosis Formation

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and methods

2.5. Statistics

3. Results

3.1. Effect of quercetin on the cardiodynamic in MI model

3.2 Analysis of NETs formation in PMNs after MI modeling with and without Quercetin treatment.

4. Discussion

Declarations

References

Additional Declarations

Status:

Version 1