Skip to main content

Quercetin exerts cardiovascular protective effects in LPS-induced dysfunction in vivo by regulating inflammatory cytokine expression, NF-κB phosphorylation, and caspase activity

Molecular and Cellular Biochemistry volume 446, pages 43–52 (2018)Cite this article

Abstract

Impaired myocardial contractile function, one of the well-documented features of sepsis, contributes greatly to the high rate of mortality. Quercetin is widely accepted as a potential antioxidant and free radical scavenger. Epidemiologic studies have suggested that an increase in the intake of dietary Quercetin can reduce the risk of cardiac disease. However, presently there is no report yet on the influence of Quercetin on LPS-induced myocardial dysfunction in vivo. Cardiovascular protective effects of Quercetin on LPS-induced sepsis in mice were measured after intragastric administration, using normal saline as a positive control. Quercetin pretreatment significantly alleviated LPS-induced cardiac abnormalities in mice. The histopathologic findings in the present study justify the findings reported from the biochemical analyses. Our observation from the present research work reveals that Quercetin suppressed the production of proinflammatory cytokines at different levels, such as TNF-α and IL-1β, and inhibits the activation of I-κB phosphorylation, whereas the total content was not affected. Apoptotic pathways are related to Quercetin protection in the development of myocardial dysfunction. In conclusion, our findings demonstrate the adjuvant potentials of Quercetin for clinical sepsis treatment.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

LPS:

Lipopolysaccharide

EF:

Ejection fraction

NF-κB:

Nuclear factor-κB

FS:

Fractional shortening

BCA:

Bicinchoninic acid

OD:

Optical density

TNF-α:

Tumor necrosis factor-α

IL-1β:

Interleukin-beta

References

  1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310

    Article  PubMed  CAS  Google Scholar 

  2. Becker JU, Theodosis C, Jacob ST, Wira CR, Groce NE (2009) Surviving sepsis in low-income and middle-income countries: new directions for care and research. Lancet Infect Dis 9:577–582. https://doi.org/10.1016/S1473-3099(09)70135-5

    Article  PubMed  Google Scholar 

  3. Hall MW, Geyer SM, Guo CY, Panoskaltsis-Mortari A, Jouvet P, Ferdinands J, Shay DK, Nateri J, Greathouse K, Sullivan R, Tran T, Keisling S, Randolph AG, Pediatric Acute Lung I and Sepsis Investigators Network PSI (2013) Innate immune function and mortality in critically ill children with influenza: a multicenter study. Crit Care Med 41:224–236. https://doi.org/10.1097/CCM.0b013e318267633c

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD 2nd, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306:2594–2605. https://doi.org/10.1001/jama.2011.1829

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS (2014) Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock 42:383–391. https://doi.org/10.1097/SHK.0000000000000234

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign Guidelines Committee including the Pediatric S (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41:580–637. https://doi.org/10.1097/CCM.0b013e31827e83af

    Article  PubMed  Google Scholar 

  7. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP (1990) Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 113:227–242

    Article  PubMed  CAS  Google Scholar 

  8. Niu J, Azfer A, Kolattukudy PE (2008) Protection against lipopolysaccharide-induced myocardial dysfunction in mice by cardiac-specific expression of soluble Fas. J Mol Cell Cardiol 44:160–169. https://doi.org/10.1016/j.yjmcc.2007.09.016

    Article  PubMed  CAS  Google Scholar 

  9. Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A, Grabar S, Dhainaut JF, Mira JP, Chiche JD (2004) Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 32:660–665

    Article  PubMed  CAS  Google Scholar 

  10. Zaky A, Deem S, Bendjelid K, Treggiari MM (2014) Characterization of cardiac dysfunction in sepsis: an ongoing challenge. Shock 41:12–24. https://doi.org/10.1097/SHK.0000000000000065

    Article  PubMed  Google Scholar 

  11. Lu J, Zheng YL, Luo L, Wu DM, Sun DX, Feng YJ (2006) Quercetin reverses D-galactose induced neurotoxicity in mouse brain. Behav Brain Res 171:251–260. https://doi.org/10.1016/j.bbr.2006.03.043

    Article  PubMed  CAS  Google Scholar 

  12. Molina MF, Sanchez-Reus I, Iglesias I, Benedi J (2003) Quercetin, a flavonoid antioxidant, prevents and protects against ethanol-induced oxidative stress in mouse liver. Biol Pharm Bull 26:1398–1402

    Article  PubMed  CAS  Google Scholar 

  13. Yang T, Kong B, Gu JW, Kuang YQ, Cheng L, Yang WT, Xia X, Shu HF (2014) Anti-apoptotic and anti-oxidative roles of quercetin after traumatic brain injury. Cell Mol Neurobiol 34:797–804. https://doi.org/10.1007/s10571-014-0070-9

    Article  PubMed  CAS  Google Scholar 

  14. Beckmann DV, Carvalho FB, Mazzanti CM, Dos Santos RP, Andrades AO, Aiello G, Rippilinger A, Graca DL, Abdalla FH, Oliveira LS, Gutierres JM, Schetinger MR, Mazzanti A (2014) Neuroprotective role of quercetin in locomotor activities and cholinergic neurotransmission in rats experimentally demyelinated with ethidium bromide. Life Sci 103:79–87. https://doi.org/10.1016/j.lfs.2014.03.033

    Article  PubMed  CAS  Google Scholar 

  15. Qu X, Qi D, Dong F, Wang B, Guo R, Luo M, Yao R (2014) Quercetin improves hypoxia-ischemia induced cognitive deficits via promoting remyelination in neonatal rat. Brain Res 1553:31–40. https://doi.org/10.1016/j.brainres.2014.01.035

    Article  PubMed  CAS  Google Scholar 

  16. Jin HB, Yang YB, Song YL, Zhang YC, Li YR (2012) Protective roles of quercetin in acute myocardial ischemia and reperfusion injury in rats. Mol Biol Rep 39:11005–11009. https://doi.org/10.1007/s11033-012-2002-4

    Article  PubMed  CAS  Google Scholar 

  17. Wan LL, Xia J, Ye D, Liu J, Chen J, Wang G (2009) Effects of quercetin on gene and protein expression of NOX and NOS after myocardial ischemia and reperfusion in rabbit. Cardiovasc Ther 27:28–33. https://doi.org/10.1111/j.1755-5922.2009.00071.x

    Article  PubMed  CAS  Google Scholar 

  18. Bartekova M, Carnicka S, Pancza D, Ondrejcakova M, Breier A, Ravingerova T (2010) Acute treatment with polyphenol quercetin improves postischemic recovery of isolated perfused rat hearts after global ischemia. Can J Physiol Pharmacol 88:465–471. https://doi.org/10.1139/y10-025

    Article  PubMed  CAS  Google Scholar 

  19. Casey LC, Balk RA, Bone RC (1993) Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771–778

    Article  PubMed  CAS  Google Scholar 

  20. Debets JM, Kampmeijer R, van der Linden MP, Buurman WA, van der Linden CJ (1989) Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med 17:489–494

    Article  PubMed  CAS  Google Scholar 

  21. Rudiger A, Singer M (2007) Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 35:1599–1608. https://doi.org/10.1097/01.CCM.0000266683.64081.02

    Article  PubMed  Google Scholar 

  22. Wang X, Zingarelli B, O’Connor M, Zhang P, Adeyemo A, Kranias EG, Wang Y, Fan GC (2009) Overexpression of Hsp20 prevents endotoxin-induced myocardial dysfunction and apoptosis via inhibition of NF-kappaB activation. J Mol Cell Cardiol 47:382–390. https://doi.org/10.1016/j.yjmcc.2009.05.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Coalson JJ, Hinshaw LB, Guenter CA, Berrell EL, Greenfield LJ (1975) Pathophysiologic responses of the subhuman primate in experimental septic shock. Lab Invest 32:561–569

    PubMed  CAS  Google Scholar 

  24. Hersch M, Gnidec AA, Bersten AD, Troster M, Rutledge FS, Sibbald WJ (1990) Histologic and ultrastructural changes in nonpulmonary organs during early hyperdynamic sepsis. Surgery 107:397–410

    PubMed  CAS  Google Scholar 

  25. Gotloib L, Shostak A, Galdi P, Jaichenko J, Fudin R (1992) Loss of microvascular negative charges accompanied by interstitial edema in septic rats’ heart. Circ Shock 36:45–56

    PubMed  CAS  Google Scholar 

  26. Solomon MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, Roberts WC, Quezado ZM, Scholz TD, Cunnion RE et al (1994) Myocardial energy metabolism and morphology in a canine model of sepsis. Am J Physiol 266:H757–H768

    PubMed  CAS  Google Scholar 

  27. Goddard CM, Allard MF, Hogg JC, Walley KR (1996) Myocardial morphometric changes related to decreased contractility after endotoxin. Am J Physiol 270:H1446–H1452

    PubMed  CAS  Google Scholar 

  28. Lancel S, Joulin O, Favory R, Goossens JF, Kluza J, Chopin C, Formstecher P, Marchetti P, Neviere R (2005) Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction. Circulation 111:2596–2604. https://doi.org/10.1161/CIRCULATIONAHA.104.490979

    Article  PubMed  CAS  Google Scholar 

  29. Kumar A, Krieger A, Symeoneides S, Kumar A, Parrillo JE (2001) Myocardial dysfunction in septic shock: Part II. Role of cytokines and nitric oxide. J Cardiothorac Vasc Anesth 15:485–511. https://doi.org/10.1053/jcan.2001.25003

    Article  PubMed  CAS  Google Scholar 

  30. Wu QL, Shen T, Ma H, Wang JK (2012) Sufentanil postconditioning protects the myocardium from ischemia-reperfusion via PI3K/Akt-GSK-3beta pathway. J Surg Res 178:563–570. https://doi.org/10.1016/j.jss.2012.05.081

    Article  PubMed  CAS  Google Scholar 

  31. Brown MA, Jones WK (2004) NF-kappaB action in sepsis: the innate immune system and the heart. Front Biosci 9:1201–1217

    Article  PubMed  CAS  Google Scholar 

  32. Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann DL, Vallejo JG (2001) In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4. J Infect Dis 183:1617–1624. https://doi.org/10.1086/320712

    Article  PubMed  CAS  Google Scholar 

  33. Kumar A, Thota V, Dee L, Olson J, Uretz E, Parrillo JE (1996) Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med 183:949–958

    Article  PubMed  CAS  Google Scholar 

  34. Yao RQ, Qi DS, Yu HL, Liu J, Yang LH, Wu XX (2012) Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem Res 37:2777–2786. https://doi.org/10.1007/s11064-012-0871-5

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. Qingdao University, Qingdao, 266071, Shandong, People’s Republic of China

    Xiqing Wei & Jun Yang

  2. Department of Cardiology, Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College Qingdao University, 20 Yudong Road, Yantai, 264000, Shandong, People’s Republic of China

    Jun Yang

  3. Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining, 273500, Shandong, People’s Republic of China

    Xiqing Wei

  4. Department of Cardiovascular Medicine, The Zoucheng People’s Hospital, 59 Qianquan Road, Jining, 273500, Shandong, People’s Republic of China

    Xiangli Meng, Yuxiang Yuan, Fengjuan Shen & Chengqiu Li

Authors
  1. Xiqing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiangli Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuxiang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fengjuan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chengqiu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JY and CL designed the study. XW, XL, YY, and CL performed the experiments and collected the data. CL and JY analyzed and interpreted the experimental data. XW and JY prepared the manuscript.

Corresponding authors

Correspondence to Chengqiu Li or Jun Yang.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wei, X., Meng, X., Yuan, Y. et al. Quercetin exerts cardiovascular protective effects in LPS-induced dysfunction in vivo by regulating inflammatory cytokine expression, NF-κB phosphorylation, and caspase activity. Mol Cell Biochem 446, 43–52 (2018). https://doi.org/10.1007/s11010-018-3271-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3271-6

Keywords

  • Myocardial dysfunction
  • LPS
  • Quercetin
  • Nuclear factor I-κBα
  • Apoptotic pathway