Advertisement

Ozonetherapy protects from in-stent coronary neointimal proliferation. Role of redoxins

      Abstract

      Background

      In-stent restenosis and poor re-endothelization usually follow percutaneous transluminal coronary angioplasty, even using drug-eluting stents, due to inflammation and oxidative stress. Medical ozone has antioxidant and anti-inflammatory properties and has not been evaluated in this context.

      Objectives

      To evaluate whether ozonotherapy might reduce restenosis following bare metal stents implantation in relation to the redoxin system in pigs.

      Methods

      Twelve male Landrace pigs (51 ± 9 kg) underwent percutaneous transluminal circumflex coronary arteries bare metal stent implantation under heparine infusion and fluoroscopical guidance, using standard techniques. Pigs were randomized to ozonetherapy (n = 6) or placebo (n = 6) treatment. Before stenting (24 h) and twice a week for 30 days post-stenting, venous blood was collected, ozonized and reinfused. Same procedure was performed in placebo group except for ozonation. Both groups received antiplatelet treatment. Histopathology and immunohistochemistry studies were performed.

      Results

      Severe inflammatory reaction and restenosis with increase in the immunohistochemical expression of thioredoxin-1 were observed in placebo group 30 days after surgery. Oppositely, ozonetherapy drastically reduced inflammatory reaction and restenosis, and showed no increase in the Trx-1 immunohistochemical expression 30 days after surgery. Immunolabeling for Prx-2 was negative in both groups. Ozonated autohemotherapy strikingly reduced restenosis 30 days following PTCA with BMS implantation in pigs.

      Conclusions

      Stimulation of the redoxin system by ozone pretreatment might neutralize oxidative damage from the start and increase antioxidative buffering capacity post-injury, reducing further damage and so the demand for antioxidant enzymes. Our interpretation agrees with the ozone oxidative preconditioning mechanism, extensively investigated.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hamid H.
        • Coltart J.
        ‘Miracle stents’—a future without restenosis.
        McGill J. Med. 2007; 10: 105-111
        • Lim S.Y.
        • Jeong M.H.
        • Hong S.J.
        • et al.
        Inflammation and delayed endothelialization with overlapping drug-eluting stents in a porcine model of in-stent restenosis.
        Circ. J. 2008; 72: 463-468
        • Bocci V.
        How a calculated oxidative stress can yield multiple therapeutic effects.
        Free Radic. Res. 2012; 46: 1068-1075
        • Martínez-Sánchez G.
        • Delgado-Roche L.
        • Díaz-Batista A.
        • et al.
        Effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease.
        Eur. J. Pharmacol. 2012; 691: 156-162
        • Sancak E.B.
        • Turkön H.
        • Çukur S.
        • et al.
        Major ozonated autohemotherapy preconditioning ameliorates kidney ischemia–reperfusion injury.
        Inflammation. 2015 Aug; 19: 1-9
        • Sayar I.
        • Bicer S.
        • Gursul C.
        • et al.
        Protective effects of ellagic acid and ozone on rat ovaries with an ischemia/reperfusion injury.
        J. Obstet. Gynaecol . Res. 2016; 42: 52-58
        • Bocci V.
        • Zanardia I.
        • Valacchi G.
        • et al.
        Validity of oxygen-ozone therapy as integrated medication form in chronic inflammatory diseases.
        Cardiovasc. Hematol. Disord. Drug Targets. 2015; 15: 127-138
        • Di Paolo N.
        • Bocci V.
        • Salvo D.P.
        • et al.
        Extracorporeal blood oxygenation and ozonation (EBOO): a controlled trial in patients with peripheral artery disease.
        Int. J. Artif. Organs. 2005; 28: 1039-1050
        • Schwartz R.S.
        • Chronos N.A.
        • Virmani R.
        Preclinical restenosis models and drug-eluting stents: still important, still much to learn.
        J. Am. Coll. Cardiol. 2004; 44: 1373-1385
        • Schwartz R.S.
        • Murphy J.G.
        • Edwards W.D.
        • et al.
        Restenosis after balloon angioplasty: a practical proliferative model in porcine coronary arteries.
        Circulation. 1990; 82: 2190-2200
        • Schwartz R.
        • Huber K.
        • Murphy J.
        • et al.
        Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model.
        J. Am. Coll. Cardiol. 1992; 19: 267-274
        • Elesbão J.L.
        • Pereira A.H.
        • Grüdtner M.A.
        • Meyer F.
        Morphometric analysis of swine carotid artery angioplasty with or without cobalt-chromium stent implantation.
        J. Vasc. Br. 2010; 9: 40-46
        • Versaci F.
        • Gaspardone A.
        Prevention of restenosis after stenting: the emerging role of inflammation.
        Coron. Artery Dis. 2004; 15: 307-311
        • Ouriel K.
        Peripheral arterial disease.
        Lancet. 2001; 358: 1257-1264
        • Park S.J.
        • Kang S.J.
        • Virmani R.
        • et al.
        In-stent neoatherosclerosis: a final common pathway of late stent failure.
        J. Am. Coll. Cardiol. 2012; 59: 2051-2057
        • Kimura T.
        • Yokoi H.
        • Nakagawa Y.
        • et al.
        Three-year follow-up after implantation of metallic coronary-artery stents.
        N. Engl. J. Med. 1996; 334: 561-566
        • Mowakeaa S.
        • Iskandar A.
        • Kakouros N.
        Neoatherosclerosis in very late stenosis of bare metal stent by optical coherence tomography.
        Case Rep. Cardiol. 2016; 2016: 1652065
        • Bocci V.
        • Valacchi G.
        Nrf2 activation as target to implement therapeutic treatments.
        Front Chem. 2015; 3: 4
        • Re L.
        • Martínez-Sánchez G.
        • Bordicchia M.
        • et al.
        Is ozone pre-conditioning effect linked to Nrf2/EpRE activation pathway in vivo? A preliminary result.
        Eur. J. Pharmacol. 2014; 742: 158-162
        • Pecorelli A.
        • Bocci V.
        • Acquaviva A.
        • et al.
        NRF2 activation is involved in ozonated human serum upregulation of HO-1 in endothelial cells.
        Toxicol. Appl. Pharmacol. 2013; 267: 30-40
        • Sagai M.
        • Bocci V.
        Mechanisms of action involved in ozone therapy: is healing induced via a mild oxidative stress?.
        Med. Gas Res. 2011; 1: 29
        • Calabrese E.J.
        Hormetic mechanisms.
        Crit. Rev. Toxicol. 2013; 43: 580-606
        • Zhang J.
        • Guan M.
        • Xie C.
        • et al.
        Increased growth factors play a role in wound healing promoted by noninvasive oxygen-ozone therapy in diabetic patients with foot ulcers.
        Oxidative Med. Cell. Longev. 2014; 2014: 273475
        • Elvis A.M.
        • Ekta J.S.
        Ozone therapy: a clinical review.
        J. Nat. Sci. Biol. Med. 2011; 2: 66-70
        • Di Filippo C.
        • Luongo M.
        • Marfella R.
        • et al.
        Oxygen/ozone protects the heart from acute myocardial infarction through local increase of eNOS activity and endothelial progenitor cells recruitment.
        Naunyn Schmiedeberg's Arch. Pharmacol. 2010; 382: 287-291
        • Schulz S.
        • Ninke S.
        • Watzer B.
        • Nüsing R.M.
        Ozone induces synthesis of systemic prostacyclin by cyclooxygenase-2 dependent mechanism in vivo.
        Biochem. Pharmacol. 2012; 83: 506-513