Hyperlipidemia represents a major risk factor for cardiovascular diseases leading to myocardial injury. The present study aimed to illustrate the myocardial injury induced in a diabetic hyperlipidemic rat model and the effect of vitamin D3, 10-DHGD intake either individually or in combination form. Male albino rats were selected for the study, received alloxan, hypercholesterolemic diet, and categorized into four groups. The first one (DHC), received hypercholesterolemic diet only and referred to as control. The remaining groups (2, 3, 4) received vitamin D3, 10-DHGD, and combination of both, respectively. Certain biomarkers that were selected for MI evaluation included blood glucose, lipogram pattern, Copeptin, C-reactive protein, myeloperoxidase, heart fatty acid-binding protein, and histopathological changes in myocardium and aorta. Vitamin D3 and 10-DHGD intake induced significant hypoglycemic, hypolipidemic effects, decreased inflammation, and MI biomarkers. Decreased myocardial vacuoles, foam cells, and intimal lesions were also observed compared to DHC. Their combination intake induced more marked reduction in all biomarkers and showed a histopathological pattern similar to normal features of myocardium and aorta. Our findings suggest the therapeutic roles of vitamin D3, 10-DHGD, and their combination against myocardial injury in diabetic hyperlipidemic rats.
Impact statement
Hyperlipidemia represents a major risk factor for cardiovascular diseases leading to myocardial injury (MI). The present study aimed to illustrate the pattern of myocardial injury induced in diabetic hyperlipidemic rat model and the effect of vitamin D3, 10-dehydrogingerdione (10-DHGD) intake either individually or in combination form.
JiXShiSLiuBShanMTangDZhangWZhangYZhangLZhangHLuCWangY.Bioactive compounds from herbal medicines to manage dyslipidemia. Biomed Pharmacother2019;
118:109338
2.
GuptaMTummalaRGhoshRKBlumenthalCPhilipKBandyopadhyayDVenturaHDeedwaniaP.An update on pharmacotherapies in diabetic dyslipidemia. Prog Cardiovasc Dis2019;62(4), 334–341
3.
MishraRM.Determinants of cardiovascular disease and sequential decision-making for treatment among women: a Heckman's approach. SSM Popul Health2019;
7:100365
4.
FloraGDNayakMK.A brief review of cardiovascular diseases, associated risk factors and current treatment regimes. Curr Pharm Des2019;25(38),4063–4084
5.
ShattatG.A review article on hyperlipidemia: types, treatments and new drug targets. Biomed Pharmacol J2014;
7:399–409
6.
NickolasTLRadhakrishnanJAppelGB.Hyperlipidemia and thrombotic complications in patients with membranous nephropathy. Semin Nephrol2003;
23:406–11
7.
ChanDNgLL.Biomarkers in acute myocardial infarction. BMC Med2010;
8:34
8.
PilottoL.Estimation of contribution of changes in coronary care to improving survival, event rates, and coronary heart disease mortality across the WHO MONICA project populations. Ital Heart J Suppl2000;
1:836–7
9.
WangJTanG-JHanL-NBaiY-YHeMLiuH-B.Novel biomarkers for cardiovascular risk prediction. J Geriatr Cardiol2017;
14:135–50
10.
O'DonoghueMLMorrowDACannonCPJarolimPDesaiNRSherwoodMWMurphySAGersztenRESabatineMS.Multimarker risk stratification in patients with acute myocardial infarction. J Am Heart Assoc2016;
5:e002586
11.
DasUN.Heart-type fatty acid-binding protein (H-FABP) and coronary heart disease. Indian Heart J2016;
68:16–8
12.
KleineAHGlatzJFVan NieuwenhovenFAVan der VusseGJ.Release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. Mol Cell Biochem1992;
116:155–62
13.
VupputuriASekharSKrishnanSVenugopalKNatarajanKU.Heart-type fatty acid-binding protein (H-FABP) as an early diagnostic biomarker in patients with acute chest pain. Indian Heart J2015;
67:538–42
14.
LiCJLiJQLiangXFLiXXCuiJGYangZJGuoQCaoKJHuangJ.Point-of-care test of heart-type fatty acid-binding protein for the diagnosis of early acute myocardial infarction. Acta Pharmacol Sin2010;
31:307–12
15.
BoeckelJ-NOppermannJAnadolRFichtlschererSZeiherAMKellerT.Analyzing the release of copeptin from the heart in acute myocardial infarction using a.Sci Rep2016;
6:20812
16.
TsutamotoTWadaAMaedaKHisanagaTMaedaYFukaiDOhnishiMSugimotoYKinoshitaM.Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation1997;
96:509–16
17.
MorgenthalerNGStruckJAlonsoCBergmannA.Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem2006;
52:112–9
18.
LattucaBSyVNguyenLSBernardMZeitouniMOvertchoukPYanYHammoudiNCeccaldiAColletJ-PKerneisMDialloAMontalescotGSilvainJ.Copeptin as a prognostic biomarker in acute myocardial infarction. Int J Cardiol2019;
274:337–41
19.
ChoiHJKimMCSimDSHongYJKimJHJeongMHKimSHShinMGAhnY.Serum copeptin levels predict clinical outcomes after successful percutaneous coronary intervention in patients with acute myocardial infarction. Ann Lab Med2018;
38:538–44
20.
HasanRLindartoDSiregarGAMukhtarZ.The effect of Bay leaf extract Syzygium polyanthum (wight) Walp. on C-reactive protein (CRP) and myeloperoxidase (MPO) level in the heart of rat model of myocardial infarction. Med Glas (Zenica)2020;
17(1):41–45
21.
LibbyP.Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol2012;
32:2045–51
22.
RudolphVGoldmannBUBosCRudolphTKKlinkeAFriedrichsKLauDWegscheiderKHaddadMMeinertzTBaldusS.Diagnostic value of MPO plasma levels in patients admitted for suspected myocardial infarction. Int J Cardiol2011;
153:267–71
23.
SacksFM.Do statins play a role in the early management of the acute coronary syndrome?Eur Heart J Suppl2004;
6:A32–A36
24.
YaoHLvJ.Statin attenuated myocardial inflammation induced by PM2.5 in rats. Acta Cardiologica Sinica2017;
33:637–45
25.
CozleaDLFarcasDMNagyAKeresztesiAATifreaRCozleaLCarascaE.The impact of C reactive protein on global cardiovascular risk on patients with coronary artery disease. Curr Health Sci J2013;
39:225–31
26.
GronholdtMLSillesenHWiebeBMLaursenHNordestgaardBG.Increased acute phase reactants are associated with levels of lipoproteins and increased carotid plaque volume. Eur J Vasc Endovasc Surg2001;
21:227–34
27.
MiyaoYYasueHOgawaHMisumiIMasudaTSakamotoTMoritaE.Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J1993;
126:1299–304
28.
ElseweidyMMElswefySEYounisNNTarekS.The modulation of PCSK-9 and GAGs by 10-dehydrogingerdione and pentoxifylline in hyperlipidemic rabbits. Nat Prod Res2018;1–6
29.
El-SeweidyMMAskerM-SEldahmySIAtteiaHHAbdallahMA.Haemostatic risk factors in dyslipidemic rabbits: role of 10-dehydrogingerdione as a new hypolipemic agent. J Thromb Thrombolysis2015;
39:196–202
30.
ElseweidyMMMohamedHEElrashidyRAAtteiaHHElnagarGMAliA-M.Potential therapeutic roles of 10-dehydrogingerdione and/or pentoxifylline against calcium deposition in aortic tissues of high dietary cholesterol-fed rabbits. Mol Cell Biochem2019;
453:131–42
31.
ElseweidyMMElswefySEYounisNNTarekS.Contribution of aorta glycosaminoglycans and PCSK9 to hyperlipidemia in experimental rabbits: the role of 10-dehdrogingerdione as effective modulator. Mol Biol Rep2019;
46:3921–28
32.
ElseweidyMMZaghloulMSYounisNN.10-DHGD ameliorates cisplatin-induced nephrotoxicity in rats. Biomed Pharmacother2016;
83:241–46
33.
SaponaroFMarcocciCZucchiR.Vitamin D status and cardiovascular outcome. J Endocrinol Invest2019;
34.
KunadianVFordGABawamiaBQiuWMansonJE.Vitamin D deficiency and coronary artery disease: a review of the evidence. Am Heart J2014;
167:283–91
35.
LiuYPengWLiYWangBYuJXuZ.Vitamin D deficiency harms patients with coronary heart disease by enhancing inflammation. Med Sci Monit2018;
24:9376–84
36.
ReidIRBollandMJ.Role of vitamin D deficiency in cardiovascular disease. Heart2012;
98:609–14
37.
ZittermannA.Vitamin D and cardiovascular disease. Anticancer Res2014;
34:4641–8
38.
Yousefi RadEDjalaliMKoohdaniFSaboor-YaraghiAAEshraghianMRJavanbakhtMHSabooriSZareiMHosseinzadeh-AttarMJ.The effects of vitamin D supplementation on glucose control and insulin resistance in patients with diabetes type 2: a randomized clinical trial study. Iran J Public Health2014;
43:1651–6
39.
LenzenS.The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia2008;
51:216–26
40.
RohillaAAliS.Alloxan induced diabetes: mechanisms and effects. Int J Res Pharm Biomed Sci2012;
3(2):819–23
41.
YangWShiHZhangJShenZZhouGHuM.Effects of the duration of hyperlipidemia on cerebral lipids, vessels and neurons in rats. Lipids Health Dis2017;
16:26
42.
ElseweidyMMZeinNAldhamySEElsawyMMSaeidSA.Policosanol as a new inhibitor candidate for vascular calcification in diabetic hyperlipidemic rats. Exp Biol Med (Maywood)2016;
241:1943–49
43.
Fallah HuseiniHAbdolghaffariAHAhwaziMJasemiEYaghoobiMZiaeeM.Topical application of Teucrium polium can improve wound healing in diabetic rats. Int J Lower Extremity Wounds2019;19(2):132--138
44.
Rodríguez-MagañaMPCordero-PérezPRivas-MoralesCOranday-CárdenasMAMoreno-PeñaDPGarcía-HernándezDGLeos-RivasC.Hypoglycemic activity of Tilia americana, Borago Officinalis, Chenopodium nuttalliae, and piper sanctum on wistar rats. J Diabetes Res2019;
2019:7836820–20
45.
ShahNAKhanMR.Antidiabetic effect of Sida cordata in alloxan induced diabetic rats. Biomed Res Int2014;
2014:671294–94
46.
Ben SalemMBen Abdallah KolsiRDhouibiRKsoudaKCharfiSYaichMHammamiSSahnounZZeghalKMJamoussiKAffesH.Protective effects of Cynara scolymus leaves extract on metabolic disorders and oxidative stress in alloxan-diabetic rats. BMC Complement Altern Med2017;
17:328–28
47.
Guadarrama-LópezALValdés-RamosRMartínez-CarrilloBE.Type 2 diabetes, PUFAs, and vitamin D: their relation to inflammation. J Immunol Res2014;
2014:860703–03
48.
QinnaNABadwanAA.Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats.Drug Des Devel Ther2015;
9:2515–25
49.
DeepaPRVaralakshmiP.Atheroprotective effect of exogenous heparin-derivative treatment on the aortic disturbances and lipoprotein oxidation in hypercholesterolemic diet fed rats. Clin Chim Acta2005;
355:119–30
50.
FarhangiMAMesgari-AbbasiMNameniGHajiluianGShahabiP.The effects of vitamin D administration on brain inflammatory markers in high fat diet induced obese rats. BMC Neurosci2017;
18:81
51.
FarhangiMANameniGHajiluianGMesgari-AbbasiM.Cardiac tissue oxidative stress and inflammation after vitamin D administrations in high fat-diet induced obese rats. BMC Cardiovasc Disord2017;
17:161
52.
SalumEKampusPZilmerMEhaJButlinMAvolioAPPõdramägiTArendAAunapuuMKalsJ.Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes. Cardiovasc Diabetol2012;
11:58
53.
ChoiS-YParkG-SLeeSYKimJYKimYK.The conformation and CETP inhibitory activity of [10]-dehydrogingerdione isolated from Zingiber officinale. Arch Pharm Res2011;
34:727–31
54.
ElseweidyMMAbdallahFRYounisNNAldohmySKassemHM.10-Dehydrogingerdione raises HDL-cholesterol through a CETP inhibition and wards off oxidation and inflammation in dyslipidemic rabbits. Atherosclerosis2013;
231:334–40
55.
FischerAHJacobsonKARoseJZellerR.Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc2008;
2008:pdb prot4986
56.
ChaitAGoldbergI.Treatment of dyslipidemia in diabetes: recent advances and remaining questions. Curr Diab Rep2017;
17:112
57.
OjiakoOAChikeziePCOgbujiAC.Blood glucose level and lipid profile of alloxan-induced hyperglycemic rats treated with single and combinatorial herbal formulations. J Tradit Complement Med2016;
6:184–92
58.
LinMJChangYJChenCYHuangCCChuangTYWuHP.Influence of hypercholesterolemia and diabetes on long-term outcome in patients with stable coronary artery disease receiving percutaneous coronary intervention. Medicine2019;
98:e16927
59.
IftikharAAslamBIftikharMMajeedWBatoolMZahoorBAmnaNGoharHLatifI.Effect of Caesalpinia bonduc polyphenol extract on alloxan-induced diabetic rats in attenuating hyperglycemia by upregulating insulin secretion and inhibiting JNK signaling pathway. Oxid Med Cell Longev2020;
2020:9020219
60.
KohEMKimHJKimSChoiWHChoiYHRyuSYKimYSKohWSParkSY.Modulation of macrophage functions by compounds isolated from Zingiber officinale. Planta Med2009;
75:148–51
61.
LeeHYParkSHLeeMKimHJRyuSYKimNDHwangBYHongJTHanSBKimY.1-Dehydro-[10]-gingerdione from ginger inhibits IKKbeta activity for NF-kappaB activation and suppresses NF-kappaB-regulated expression of inflammatory genes. Br J Pharmacol2012;
167:128–40
62.
BekkouchOHarnafiMTouissIKhatibSHarnafiHAlemCAmraniS.In vitro antioxidant and in vivo lipid-lowering properties of Zingiber officinale crude aqueous extract and methanolic fraction: a follow-up study. Evid Based Complement Alternat Med2019;
2019:9734390
63.
ElseweidyMMMohamedHEElrashidyRAAtteiaHHElnagarGMAliAE.Potential therapeutic roles of 10-dehydrogingerdione and/or pentoxifylline against calcium deposition in aortic tissues of high dietary cholesterol-fed rabbits. Mol Cell Biochem2018;
453(1-2):131–142
64.
ElseweidyMMAminRSAtteiaHHAliMA.Vitamin D3 intake as regulator of insulin degrading enzyme and insulin receptor phosphorylation in diabetic rats. Biomed Pharmacother2017;
85:155–59
65.
JohnsonJAGrandeJPRochePCKumarR.Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28k in human and rat pancreas. Am J Physiol1994;
267:E356–60
66.
MilajerdiAOstadmohammadiVAmirjaniSKolahdoozFAsemiZ.The effects of vitamin D treatment on glycemic control, serum lipid profiles, and C-reactive protein in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials. Int Urol Nephrol2019;
51:1567–80
67.
Al-ShoumerKAAl-EssaTM.Is there a relationship between vitamin D with insulin resistance and diabetes mellitus?WJD2015;
6:1057–64
68.
KumarSDaviesMZakariaYMawerEBGordonCOlukogaAOBoultonAJ.Improvement in glucose tolerance and beta-cell function in a patient with vitamin D deficiency during treatment with vitamin D. Postgrad Med J1994;
70:440–3
69.
MaestroBMoleroSBajoSDavilaNCalleC.Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3). Cell Biochem Funct2002;
20:227–32
70.
DerakhshanianHDjalaliMMohammad HassanMHAlvandiEEshraghianMRMirshafieyANadimiHJahanabadiSZareiMDjazayeryA.Vitamin D suppresses cellular pathways of diabetes complication in liver. Iranian J Basic Med Sci2019;
22:690–94
71.
DunlopTWVaisanenSFrankCMolnarFSinkkonenLCarlbergC.The human peroxisome proliferator-activated receptor Delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol2005;
349:248–60
72.
DerakhshanianHDjazayeryAJavanbakhtMHEshraghianMRMirshafieyAJahanabadiSGhadbeigiSZareiMAlvandiEDjalaliM.Vitamin D downregulates key genes of diabetes complications in cardiomyocyte. J Cell Physiol2019;
234:21352–58
73.
NingCLiuLLvGYangYZhangYYuRWangYZhuJ.Lipid metabolism and inflammation modulated by vitamin D in liver of diabetic rats. Lipids Health Dis2015;
14:31
74.
ImgaNNKarciACOztasDBerkerDGulerS.Effects of vitamin D supplementation on insulin resistance and dyslipidemia in overweight and obese premenopausal women. AOMS2019;
15:598–606
75.
Abdel-RehimWMEl-TahanRAEl-TarawyMAShehataRRKamelMA.The possible antidiabetic effects of vitamin D receptors agonist in rat model of type 2 diabetes. Mol Cell Biochem2019;
450:105–12
76.
CantornaMTZhuYFroicuMWittkeA.Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr2004;
80:1717S–20S
77.
LiefaardMCLigthartSVitezovaAHofmanAUitterlindenAGKiefte-de JongJCFrancoOHZillikensMCDehghanA.Vitamin D and C-reactive protein: a Mendelian randomization study. PLoS One2015;
10:e0131740
78.
ZhangYLeungDYRichersBNLiuYRemigioLKRichesDWGolevaE.Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol2012;
188:2127–35
79.
ZhouWYeS-DChenCWangW.Involvement of RBP4 in diabetic atherosclerosis and the role of vitamin D intervention. J Diabetes Res2018;
2018:7329861
80.
SabryHHSabryJHDaifallaAEHAklEMHamedAMTorkyAA.Serum markers for asymptomatic atherosclerosis in Egyptian psoriatic patients: study controlled by Doppler estimation of carotid intima-media thickness. Vasc Health Risk Manag2018;
14:145–52
81.
Wei-HongTMin-ChangGZhenXJieS.Pharmacological and pharmacokinetic studies with vitamin D-loaded nanoemulsions in asthma model. Inflammation2014;
37:723–28
82.
da SilvaJLGPassosDFBernardesVMCabralFLSchimitesPGManzoniAGde OliveiraEGde Bona da SilvaCBeckRCRJantschMHMacielRMLealD.Co-Nanoencapsulation of vitamin D3 and curcumin regulates inflammation and purine metabolism in a model of arthritis. Inflammation2019;
42:1595–610
83.
Mellor-PitaSTutor-UretaPRosadoSAlkadiKGranadoFJimenez-OrtizCCastejonR.Calcium and vitamin D supplement intake may increase arterial stiffness in systemic lupus erythematosus patients. Clin Rheumatol2019;
38:1177–86
84.
NiizumaSIwanagaYYahataTMiyazakiS.Renocardiovascular biomarkers: from the perspective of managing chronic kidney disease and cardiovascular disease. Front Cardiovasc Med2017;
4:10
85.
ReinstadlerSJKlugGFeistritzerH-JMetzlerBMairJ.Copeptin testing in acute myocardial infarction: ready for routine use?Dis Markers2015;
2015:614145
