N-acetylcysteine with low-dose estrogen reduces cardiac ischemia-reperfusion injury

in Journal of Endocrinology

Correspondence should be addressed to N Chattipakorn: nchattip@gmail.com
Restricted access

Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 1029 1029 68
Full Text Views 49 49 1
PDF Downloads 29 29 1
  • AnderssonDCFauconnierJYamadaTLacampagneAZhangSJKatzAWesterbladH 2011 Mitochondrial production of reactive oxygen species contributes to the beta-adrenergic stimulation of mouse cardiomycytes. Journal of Physiology 589 . (https://doi.org/10.1113/jphysiol.2010.202838)

    • Search Google Scholar
    • Export Citation
  • ApaijaiNChindaKPaleeSChattipakornSChattipakornN 2014 Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. PLoS ONE 9 e102374. (https://doi.org/10.1371/journal.pone.0102374)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BartekovaMBarancikMFerenczyovaKDhallaNS 2018 Beneficial effects of N-acetylcysteine and N-mercaptopropionylglycine on ischemia reperfusion injury in the heart. Current Medicinal Chemistry 25 . (https://doi.org/10.2174/0929867324666170608111917)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bonithon-KoppCScarabinPYDarneBMalmejacAGuizeL 1990 Menopause-related changes in lipoproteins and some other cardiovascular risk factors. International Journal of Epidemiology 19 . (https://doi.org/10.1093/ije/19.1.42)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • CamposCCasaliKRBaraldiDConzattiAAraújoASKhaperNLlesuySRigattoKBelló-KleinA 2014 Efficacy of a low dose of estrogen on antioxidant defenses and heart rate variability. Oxidative Medicine and Cellular Longevity 2014 218749. (https://doi.org/10.1155/2014/218749)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • CrandallC 2003 Low-dose estrogen therapy for menopausal women: a review of efficacy and safety. Journal of Women’s Health 12 . (https://doi.org/10.1089/154099903322447701)

    • Search Google Scholar
    • Export Citation
  • FukumotoTTawaMYamashitaNOhkitaMMatsumuraY 2013 Protective effects of 17beta-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow through the non-genomic estrogen receptor/nitric oxide-mediated pathway in the rat heart. European Journal of Pharmacology 699 . (https://doi.org/10.1016/j.ejphar.2012.11.042)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • IncharoenTThephinlapCSrichairatanakoolSChattipakornSWinichagoonPFucharoenSVadolasJChattipakornN 2007 Heart rate variability in beta-thalassemic mice. International Journal of Cardiology 121 . (https://doi.org/10.1016/j.ijcard.2006.08.076)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • KonstantinidisKWhelanRSKitsisRN 2012 Mechanisms of cell death in heart disease. Arteriosclerosis Thrombosis and Vascular Biology 32 . (https://doi.org/10.1161/ATVBAHA.111.224915)

    • Search Google Scholar
    • Export Citation
  • KorouLMAgrogiannisGPantopoulouAVlachosISIliopoulosDKaratzasTPerreaDN 2010 Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice. Lipids in Health and Disease 9 23. (https://doi.org/10.1186/1476-511X-9-23)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KrulSPJBergerWRVeldkampMWDriessenAHGWildeAAMDenekeTde BakkerJMTCoronelRde GrootJR 2015 Treatment of atrial and ventricular arrhythmias through autonomic modulation. JACC: Clinical Electrophysiology 1 . (https://doi.org/10.1016/j.jacep.2015.09.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • KumarSSitasawadSL 2009 N-acetylcysteine prevents glucose/glucose oxidase-induced oxidative stress, mitochondrial damage and apoptosis in H9c2 cells. Life Sciences 84 . (https://doi.org/10.1016/j.lfs.2008.12.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • LeeTMLaiPYChangNC 2010 Effect of N-acetylcysteine on sympathetic hyperinnervation in post-infarcted rat hearts. Cardiovascular Research 85 . (https://doi.org/10.1093/cvr/cvp286)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • LeeTMLinSZChangNC 2013 Both PKA and Epac pathways mediate N-acetylcysteine-induced connexin43 preservation in rats with myocardial infarction. PLoS ONE 8 e71878. (https://doi.org/10.1371/journal.pone.0071878)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LinCCYinMC 2008 Effects of cysteine-containing compounds on biosynthesis of triacylglycerol and cholesterol and anti-oxidative protection in liver from mice consuming a high-fat diet. British Journal of Nutrition 99 . (https://doi.org/10.1017/S0007114507793881)

    • Search Google Scholar
    • Export Citation
  • MaYGaoMLiuD 2016 N-acetylcysteine protects mice from high fat diet-induced metabolic disorders. Pharmaceutical Research 33 . (https://doi.org/10.1007/s11095-016-1941-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • MatthewsDRHoskerJPRudenskiASNaylorBATreacherDFTurnerRC 1985 Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28 . (https://doi.org/10.1007/BF00280883)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • NAMS 2017 Hormone Therapy Position Statement Advisory Panel 2017 The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 24 . (https://doi.org/10.1097/GME.0000000000000921)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • OrhanGYapiciNYukselMSarginMSenaySYalcinASAykacZAkaSA 2006 Effects of N-acetylcysteine on myocardial ischemia-reperfusion injury in bypass surgery. Heart and Vessels 21 . (https://doi.org/10.1007/s00380-005-0873-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • OzdemirSCelikCGorkemliHKiyiciAKayaB 2009 Compared effects of surgical and natural menopause on climacteric symptoms, osteoporosis, and metabolic syndrome. International Journal of Gynaecology and Obstetrics 106 . (https://doi.org/10.1016/j.ijgo.2009.03.016)

    • Search Google Scholar
    • Export Citation
  • RiessMLRhodesSSStoweDFAldakkakMCamaraAKS 2009 Comparison of cumulative planimetry versus manual dissection to assess experimental infarct size in isolated hearts. Journal of Pharmacological and Toxicological Methods 60 . (https://doi.org/10.1016/j.vascn.2009.05.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Riojas-HernandezABernal-RamirezJRodriguez-MierDMorales-MarroquinFEDominguez-BarraganEMBorja-VillaCRivera-AlvarezIGarcia-RivasGAltamiranoJGarciaN 2015 Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker Fa/fa rats with type 2 diabetes. Life Sciences 141 . (https://doi.org/10.1016/j.lfs.2015.09.018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • RiveraCMGrossardtBRRhodesDJBrownRDJRogerVLMeltonLJ3rdRoccaWA 2009 Increased cardiovascular mortality after early bilateral oophorectomy. Menopause 16 . (https://doi.org/10.1097/gme.0b013e31818888f7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • SivasinprasasnSSa-nguanmooPPratchayasakulWKumfuSChattipakornSCChattipakornN 2015 Obese-insulin resistance accelerates and aggravates cardiometabolic disorders and cardiac mitochondrial dysfunction in estrogen-deprived female rats. Age 37 28. (https://doi.org/10.1007/s11357-015-9766-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SivasinprasasnSSa-NguanmooPPongkanWPratchayasakulWChattipakornSCChattipakornN 2016 Estrogen and DPP4 inhibitor, but not metformin, exert cardioprotection via attenuating cardiac mitochondrial dysfunction in obese insulin-resistant and estrogen-deprived female rats. Menopause 23 . (https://doi.org/10.1097/GME.0000000000000640)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • SivasinprasasnSTanajakPPongkanWPratchayasakulWChattipakornSCChattipakornN 2017 DPP-4 inhibitor and estrogen share similar efficacy against cardiac ischemic-reperfusion injury in obese-insulin resistant and estrogen-deprived female rats. Scientific Reports 7 44306. (https://doi.org/10.1038/srep44306)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SovariAARutledgeCAJeongEMDolmatovaEArasuDLiuHVahdaniNGuLZandiehSXiaoL 2013 Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death. Circulation: Arrhythmia and Electrophysiology 6 . (https://doi.org/10.1161/CIRCEP.112.976787)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • StuenkelCADavisSRGompelALumsdenMAMuradMHPinkertonJVSantenRJ 2015 Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 100 . (https://doi.org/10.1210/jc.2015-2236)

    • Search Google Scholar
    • Export Citation
  • SzkudlinskaMAvon FrankenbergADUtzschneiderKM 2016 The antioxidant N-acetylcysteine does not improve glucose tolerance or beta-cell function in type 2 diabetes. Journal of Diabetes and its Complications 30 . (https://doi.org/10.1016/j.jdiacomp.2016.02.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • ThummasornSKumfuSChattipakornSChattipakornN 2011 Granulocyte-colony stimulating factor attenuates mitochondrial dysfunction induced by oxidative stress in cardiac mitochondria. Mitochondrion 11 . (https://doi.org/10.1016/j.mito.2011.01.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • TuncayEOkatanENToyATuranB 2014 Enhancement of cellular antioxidant-defence preserves diastolic dysfunction via regulation of both diastolic Zn2+ and Ca2+ and prevention of RyR2-leak in hyperglycemic cardiomyocytes. Oxidative Medicine and Cellular Longevity 2014 290381. (https://doi.org/10.1155/2014/290381)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • VillagarcíaHGCastroMCArbelaezLGSchinellaGMassaMLSpinediEFranciniF 2018 N-acetyl-l-cysteine treatment efficiently prevented pre-diabetes and inflamed-dysmetabolic liver development in hypothalamic obese rats. Life Sciences 199 . (https://doi.org/10.1016/j.lfs.2018.03.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • VitaleCMendelsohnMERosanoGMC 2009 Gender differences in the cardiovascular effect of sex hormones. Nature Reviews: Cardiology 6 . (https://doi.org/10.1038/nrcardio.2009.105)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • VogelHMirhashemiFLiehlBTaugnerFKluthOKlugeRJoostH-GSchurmannA 2013 Estrogen deficiency aggravates insulin resistance and induces beta-cell loss and diabetes in female New Zealand obese mice. Hormone and Metabolic Research 45 . (https://doi.org/10.1055/s-0032-1331700)

    • Search Google Scholar
    • Export Citation
  • XuJXiangQLinGFuXZhouKJiangPZhengSWangT 2012 Estrogen improved metabolic syndrome through down-regulation of VEGF and HIF-1alpha to inhibit hypoxia of periaortic and intra-abdominal fat in ovariectomized female rats. Molecular Biology Reports 39 . (https://doi.org/10.1007/s11033-012-1665-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhaiPEurellTECotthausRJefferyEHBahrJMGrossDR 2000 Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. American Journal of Physiology: Heart and Circulatory Physiology 279 H2766H2775. (https://doi.org/10.1152/ajpheart.2000.279.6.H2766)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ZhangFLauSSMonksTJ 2011 The cytoprotective effect of N-acetyl-L-cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis. Toxicological Sciences 120 . (https://doi.org/10.1093/toxsci/kfq364)

    • Search Google Scholar
    • Export Citation