Internal and Emergency Medicine

, Volume 13, Issue 5, pp 647–649 | Cite as

Oxidative stress and inflammation: new molecular targets for cardiovascular diseases

  • Matteo BecattiEmail author
  • Amanda Mannucci
  • Niccolò Taddei
  • Claudia Fiorillo

Coronary artery disease (CAD) is the underlying condition in most acute coronary events and the leading cause of death in developed countries [1]. The previous studies have shown that oxidative stress, a condition caused by an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems and closely associated with many other chronic and acute disorders [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12], contributes to the initiation and progression of endothelial dysfunction and atherogenesis [13]. Indeed, ROS can damage every cell component, such as lipids, proteins, and DNA, and can also trigger pro-inflammatory cytokine production.

In many pathogenetic events of atherosclerosis such as endothelial dysfunction, low-density lipoprotein oxidation (OxLDL) [14], vascular smooth muscle cell proliferation, platelet aggregation and inflammation, and ROS, may play pivotal roles [15].

Inflammation-induced endothelial injury emerges as a key factor connecting chronic inflammation and thrombosis [16, 17]. However, its pathogenic mechanisms still remain a matter of debate. Many studies support oxidative stress and inflammation as interconnected processes that co-exist in the inflamed milieu [16, 17, 18]. ROS are released by inflammatory cells at the site of inflammation leading to oxidative damage; on the other hand, ROS production enhances pro-inflammatory responses. In the earliest phases of atherogenesis, neutrophils are recruited by the dysfunctional endothelial surface, where they increase ROS production and invade the vessel wall. After extravasation, neutrophils sustain a vicious cycle leading to chronic inflammation and increased plaque vulnerability by releasing oxidative enzymes, ROS, and chemokines [18].

Neutrophil extracellular traps (NETs) have been identified in 2004 as a new neutrophil pathogen-killing mechanism, and have been proven beneficial against infections [19]. NETs are extracellular DNA fibers comprising histones and neutrophil antimicrobial proteins. Extracellular DNA traps are also observed in inflammatory but noninfectious diseases, like autoimmune diseases [20] or psoriasis [21]. New emerging data describe NETs as the key players of several vascular diseases, such as acute coronary syndrome, stroke, venous thrombosis, and atherosclerosis [22]. Indeed, NETs have been identified within atherosclerotic lesions and arterial thrombi in both human beings and animal models [17].

In line with these observations, our recent findings demonstrate the key role of neutrophil-derived ROS in thrombus formation in Behçet disease (BD) patients (a model of inflammation-induced thrombosis), supporting current concepts regarding the link between inflammation, oxidative stress, and thrombosis [17].

This issue of the IAEM includes interesting research by Mozzini et al. [23] who outline new insights on the multiple and apparently contradictory facets of nuclear factor kappa B (NF-κB) in unstable angina (UA) and on its possible mediator role in NETs formation. NF-κB is a major transcription factor involved in the inflammatory cascade [24]. Studies show a strong association between NF-κB activation and development of heart failure in both human and animal models [25, 26]. It has been reported that NF-κB is involved in the process of venous thrombosis [27], and can regulate the expression of tissue factor, which plays a crucial role in the initiation of the coagulation cascade by regulating p50/p65 heterodimer [28]. However, the role of NF-κB in NETs formation is not completely understood.

Mozzini et al. investigated the role of NF-Kb in 23 patients with UA free of symptoms after a year follow-up (UA1YFU). They assessed several oxidative stress and inflammation blood markers, describing an improvement of the inflammatory status in patients with a history of UA. In particular, they show significantly decreased levels of NF-kB, plasma oxidized low-density lipoproteins (ox-LDL), high-sensitivity C-reactive protein (hs-CRP), and double-stranded DNA (ds-DNA) plasma levels in UA1YFU patients compared to UA at baseline but not vs stable angina (SA) patients. Furthermore, among pro-inflammatory cytokines, IL-6 levels in UA1YFU patients are lower than in UA at baseline, but significantly higher if compared to SA. In contrast, IL-1β levels in UA1YFU patients are lower than UA at baseline, and no differences are found if compared to SA. According to recent literature, data by Mozzini and co-workers report an interesting link among cytokines, NF-κB, and NETs in UA after 1 year of follow-up. The reported results indicate an improvement of inflammatory conditions after 1 year follow-up of UA patients.

Based on these results, we think that a better understanding of the molecular pathways connecting inflammation and oxidative stress will open the door to new therapeutic targets for cardiovascular diseases.


Compliance with ethical standards

Conflict of interest


Statements on human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent



  1. 1.
    GBD 2013 Mortality and Causes of Death Collaborators (2015) Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 385:117–171. CrossRefGoogle Scholar
  2. 2.
    Magherini F, Abruzzo PM, Puglia M, Bini L, Gamberi T, Esposito F, Veicsteinas A, Marini M, Fiorillo C, Gulisano M, Modesti A (2012) Proteomic analysis and protein carbonylation profile in trained and untrained rat muscles. J Proteom 75:978–992. CrossRefGoogle Scholar
  3. 3.
    Becatti M, Boccalini G, Pini A, Fiorillo C, Bencini A, Bani D, Nistri S (2015) Protection of coronary endothelial cells from cigarette smoke-induced oxidative stress by a new Mn(II)-containing polyamine–polycarboxilate scavenger of superoxide anion. Vasc Pharmacol 75:19–28. CrossRefGoogle Scholar
  4. 4.
    Emmi G, Silvestri E, Squatrito D, Amedei A, Niccolai E, D’Elios MM, Della Bella C, Grassi A, Becatti M, Fiorillo C, Emmi L, Vaglio A, Prisco D (2015) Thrombosis in vasculitis: from pathogenesis to treatment. Thromb J 13:15. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Becatti M, Marcucci R, Bruschi G, Taddei N, Bani D, Gori AM, Giusti B, Gensini GF, Abbate R, Fiorillo C (2014) Oxidative modification of fibrinogen is associated with altered function and structure in the subacute phase of myocardial infarction. Arterioscler Thromb Vasc Biol 34:1355–1361. CrossRefPubMedGoogle Scholar
  6. 6.
    Becatti M, Fiorillo C, Gori AM, Marcucci R, Paniccia R, Giusti B, Violi F, Pignatelli P, Gensini GF, Abbate R (2013) Platelet and leukocyte ROS production and lipoperoxidation are associated with high platelet reactivity in non-ST elevation myocardial infarction (NSTEMI) patients on dual antiplatelet treatment. Atherosclerosis 231:392–400. CrossRefPubMedGoogle Scholar
  7. 7.
    Barygina VV, Becatti M, Soldi G, Prignano F, Lotti T, Nassi P, Wright D, Taddei N, Fiorillo C (2013) Altered redox status in the blood of psoriatic patients: involvement of NADPH oxidase and role of anti-TNF-α therapy. Redox Rep 18:100–106. CrossRefPubMedGoogle Scholar
  8. 8.
    Fiorillo C, Nediani C, Ponziani V, Giannini L, Celli A, Nassi N, Formigli L, Perna AM, Nassi P (2005) Cardiac volume overload rapidly induces oxidative stress-mediated myocyte apoptosis and hypertrophy. Biochim Biophys Acta 1741:173–182. CrossRefPubMedGoogle Scholar
  9. 9.
    Barygina V, Becatti M, Lotti T, Moretti S, Taddei N, Fiorillo C (2015) Treatment with low-dose cytokines reduces oxidative-mediated injury in perilesional keratinocytes from vitiligo skin. J Dermatol Sci 79:163–170. CrossRefPubMedGoogle Scholar
  10. 10.
    Becatti M, Marcucci R, Gori AM, Mannini L, Grifoni E, Alessandrello Liotta A, Sodi A, Tartaro R, Taddei N, Rizzo S, Prisco D, Abbate R, Fiorillo C (2016) Erythrocyte oxidative stress is associated with cell deformability in patients with retinal vein occlusion. J Thromb Haemost 14:2287–2297. CrossRefPubMedGoogle Scholar
  11. 11.
    Fiorillo C, Becatti M, Attanasio M, Lucarini L, Nassi N, Evangelisti L, Porciani MC, Nassi P, Gensini GF, Abbate R, Pepe G (2010) Evidence for oxidative stress in plasma of patients with Marfan syndrome. Int J Cardiol 145:544–546. CrossRefPubMedGoogle Scholar
  12. 12.
    Fiorillo C, Pace S, Ponziani V, Nediani C, Perna AM, Liguori P, Cecchi C, Nassi N, Donzelli GP, Formigli L, Nassi P (2002) Poly(ADP-ribose) polymerase activation and cell injury in the course of rat heart heterotopic transplantation. Free Radic Res 36:79–87. CrossRefPubMedGoogle Scholar
  13. 13.
    Yang X, Li Y, Li Y, Ren X, Zhang X, Hu D, Gao Y, Xing Y, Shang H (2017) Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol 8:600. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Choi SH, Sviridov D, Miller YI (2017) Oxidized cholesteryl esters and inflammation. Biochim Biophys Acta 1862:393–397. CrossRefGoogle Scholar
  15. 15.
    Panth N, Paudel KR, Parajuli K (2016) Reactive oxygen species: a key hallmark of cardiovascular disease. Adv Med 2016:9152732. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Aksu K, Donmez A, Keser G (2012) Inflammation-induced thrombosis: mechanisms, disease associations and management. Curr Pharm Des 18:1478–1493CrossRefPubMedGoogle Scholar
  17. 17.
    Becatti M, Emmi G, Silvestri E, Bruschi G, Ciucciarelli L, Squatrito D, Vaglio A, Taddei N, Abbate R, Emmi L, Goldoni M, Fiorillo C, Prisco D (2016) Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet disease. Circulation 133:302–311. CrossRefPubMedGoogle Scholar
  18. 18.
    Bonaventura A, Liberale L, Carbone F, Vecchié A, Diaz-Cañestro C, Camici GG, Montecucco F, Dallegri F (2018) The pathophysiological role of neutrophil extracellular traps in inflammatory diseases. Thromb Haemost 118:6–27. CrossRefPubMedGoogle Scholar
  19. 19.
    Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V (2006) DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16:396–400. CrossRefGoogle Scholar
  20. 20.
    Lee KH, Kronbichler A, Park DD, Park Y, Moon H, Kim H, Choi JH, Choi Y, Shim S, Lyu IS, Yun BH, Han Y, Lee D, Lee SY, Yoo BH, Lee KH, Kim TL, Kim H, Shim JS, Nam W, So H, Choi S, Lee S, Shin JI (2017) Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review. Autoimmun Rev 16:1160–1173. CrossRefPubMedGoogle Scholar
  21. 21.
    Hu SC, Yu HS, Yen FL, Lin CL, Chen GS, Lan CC (2016) Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes. Sci Rep 6:31119. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mozzini C, Garbin U, Fratta Pasini AM, Cominacini L (2017) An exploratory look at NETosis in atherosclerosis. Intern Emerg Med 12:13–22. CrossRefPubMedGoogle Scholar
  23. 23.
    Mozzini C, Garbin U, Stranieri C, Salandini G, Pesce G, Fratta Pasini AM, Cominacini L (2018) Nuclear factor kappa B in patients with a history of unstable angina: case reopened (IAEM-D-17-00427R2) Google Scholar
  24. 24.
    Becatti M, Prignano F, Fiorillo C, Pescitelli L, Nassi P, Lotti T, Taddei N (2010) The involvement of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: protective effects of curcumin and capsaicin. Antioxid Redox Signal 13:1309–1321. CrossRefPubMedGoogle Scholar
  25. 25.
    Frantz S, Fraccarollo D, Wagner H, Behr TM, Jung P, Angermann CE, Ertl G, Bauersachs J (2003) Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure. Cardiovasc Res 57:749–756. CrossRefPubMedGoogle Scholar
  26. 26.
    Grabellus F, Levkau B, Sokoll A, Welp H, Schmid C, Deng MC, Takeda A, Breithardt G, Baba HA (2002) Reversible activation of nuclear factor-kappaB in human end-stage heart failure after left ventricular mechanical support. Cardiovasc Res 53:124–130CrossRefPubMedGoogle Scholar
  27. 27.
    Zhai K, Tang Y, Zhang Y, Li F, Wang Y, Cao Z, Yu J, Kou J, Yu B (2015) NMMHC IIA inhibition impedes tissue factor expression and venous thrombosis via Akt/GSK3β-NF-κB signalling pathways in the endothelium. Thromb Haemost 114:173–185. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li YD, Ye BQ, Zheng SX, Wang JT, Wang JG, Chen M, Liu JG, Pei XH, Wang LJ, Lin ZX, Gupta K, Mackman N, Slungaard A, Key NS, Geng JG (2009) NF-kappaB transcription factor p50 critically regulates tissue factor in deep vein thrombosis. J Biol Chem 284:4473–4483. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© SIMI 2018

Authors and Affiliations

  1. 1.Department of Experimental and Clinical Biomedical Sciences “Mario Serio”University of FlorenceFlorenceItaly

Personalised recommendations