Abstract
Oxidative stress and fibrosis foster the development of cardiovascular disease (CVD) in diabetes. Atorvastatin protects against cardiovascular diseases in diabetes patients. However, the mechanisms are not completely known. This study evaluated the impact of atorvastatin on vascular and myocardial oxidative stress, inflammation, and fibrosis in a model of diabetes. Male Wistar rats were assigned into four groups; control rats, atorvastatin-treated rats (Ator, 40 mg/kg given by oral gavage for 6 weeks), diabetes rats (DM, single IP 40 mg/kg streptozotocin), and diabetes rats treated with atorvastatin (DM + Ator). Serum and cardiac inflammatory, oxidant, and fibrotic markers were measured. Cardiac fibrosis was evaluated by Masson trichrome stain. Streptozotocin-induced diabetes as documented by the marked elevation in blood glucose. Levels of oxidant biomarkers of serum and cardiac nitrite, cardiac nitrate, and cardiac thiobarbituric acid reactive substances (TBARS) were increased in the DM group. The use of atorvastatin reduced nitrite and TBARS levels. Serum and cardiac inflammatory factors of endothelin-1 (ET-1) were elevated in the DM group, and the use of atorvastatin reduced these increases. Cardiac C-reactive protein tended to increase in the DM group and the use of atorvastatin reduced its level. Cardiac interstitial fibrosis was increased in the DM group with a parallel increase in the platelet-derived growth factor level. The use of atorvastatin reduced cardiac fibrosis. Diabetes was associated with an increase in serum and/or myocardial markers of oxidative stress, inflammation, and fibrosis. The use of atorvastatin reduced cardiac interstitial fibrosis and decreased cardiac oxidant and inflammatory biomarkers.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
all data are presented in tables and figures. Raw data supporting the findings of this study are available on request.
Code availability
Graph Pad Prism 9.0.0 (121), La Jolla, CA, USA.
References
Aktay G, Gürsoy Ş, Uyumlu U, Ünüvar S, Ilhan N (2019) Protective effect of atorvastatin on oxidative stress in streptozotocin-induced diabetic rats independently their lipid-lowering effects. J Biochem Mol Toxicol 33:e22295. https://doi.org/10.1002/jbt.22295
Alrejaie S, Alhusaini K ( 2016) Lutein ameliorates streptozotocin-induced cardiac oxidative stress in rats. J Immunol 196(1 Supplement):216.12
Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47:693–700. https://doi.org/10.1016/j.jacc.2005.09.050
Balakumar P, Kathuria S, Taneja G, Kalra S, Mahadevan N (2012) Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol 52:83–92. https://doi.org/10.1016/j.yjmcc.2011.09.014
Ban CR, Twigg SM (2008) Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 4:575–596. https://doi.org/10.2147/vhrm.s1991
Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr (2004) Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care 27:699–703. https://doi.org/10.2337/diacare.27.3.699
Bonow L, Mann Z (eds) (2012) Braunwald’s heart disease, a textbook of cardiovascular medicine, 9th edn, volume 1 paperback. Saunders, Philadelphia
Carillion A, Feldman S, Na N, Biais M, Carpentier W, Birenbaum A, Cagnard N, Loyer X, Bonnefont-Rousselot D, Hatem S, Riou B, Amour J (2017) Atorvastatin reduces β-Adrenergic dysfunction in rats with diabetic cardiomyopathy. PLoS ONE 12:e0180103. https://doi.org/10.1371/journal.pone.0180103
Chen S, Evans T, Mukherjee K, Karmazyn M, Chakrabarti S (2000) Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors. J Mol Cell Cardiol 32:1621–1629
Chen L, Cai P, Cheng Z, Zhang Z, Fang J (2017) Pharmacological postconditioning with atorvastatin calcium attenuates myocardial ischemia/reperfusion injury in diabetic rats by phosphorylating GSK3β. Exp Ther Med 14:25–34. https://doi.org/10.3892/etm.2017.4457
Chogtu B, Magazine R, Bairy KL (2015) Statin use and risk of diabetes mellitus. World J Diabetes 6:352–357. https://doi.org/10.4239/wjd.v6.i2.352
Fang T, Guo B, Xue L, Wang L (2019) Atorvastatin prevents myocardial fibrosis in spontaneous hypertension via interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3)/endothelin-1 (ET-1) pathway. Med Sci Monit 25:318–323. https://doi.org/10.12659/msm.912032
Frangogiannis N (2020) Transforming growth factor-β in tissue fibrosis. J Exp Med 217:e20190103. https://doi.org/10.1084/jem.20190103
Frangogiannis NG (2021) Cardiac fibrosis. Cardiovasc Res 117:1450–1488. https://doi.org/10.1093/cvr/cvaa324
Furman BL (2015) Streptozotocin-induced diabetic models in mice and rats. Curr Protoc Pharmacol 70:5.47.1-5.47.20. https://doi.org/10.1002/0471141755.ph0547s70
Genovesi S, Giussani M, Orlando A, Lieti G, Viazzi F, Parati G (2022) Relationship between endothelin and nitric oxide pathways in the onset and maintenance of hypertension in children and adolescents. Pediatr Nephrol 37:537–545. https://doi.org/10.1007/s00467-021-05144-2
Ghoreshi ZA, Kabirifar R, Khodarahmi A, Karimollah A, Moradi A (2020) The preventive effect of atorvastatin on liver fibrosis in the bile duct ligation rats via antioxidant activity and down-regulation of Rac1 and NOX1. Iran J Basic Med Sci 23:30–35. https://doi.org/10.22038/ijbms.2019.33663.8047
Gorąca A, Kleniewska P, Skibska B (2016) ET-1 mediates the release of reactive oxygen species and TNF-α in lung tissue by protein kinase C α and β1. Pharmacol Rep 68:121–126. https://doi.org/10.1016/j.pharep.2015.07.007
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J (2019) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 73:3168–3209. https://doi.org/10.1016/j.jacc.2018.11.002
Guillausseau PJ, Dupuy E, Bryckaert MC, Timsit J, Chanson P, Tobelem G, Caen JP, Lubetzki J (1989) Platelet-derived growth factor (PDGF) in type 1 diabetes mellitus. Eur J Clin Invest 19:172–175. https://doi.org/10.1111/j.1365-2362.1989.tb00213.x
Gupta SK, Dongare S, Mathur R, Mohanty IR, Srivastava S, Mathur S, Nag TC (2015) Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin-induced diabetic cardiomyopathy in rats. Mol Cell Biochem 408:63–72. https://doi.org/10.1007/s11010-015-2483-2
Jiang H, Zheng H (2019) Efficacy and adverse reaction to different doses of atorvastatin in the treatment of type II diabetes mellitus. Biosci Rep 39:BSR20182371. https://doi.org/10.1042/bsr20182371
Jose J (2016) Statins and its hepatic effects: newer data, implications, and changing recommendations. J Pharm Bioallied Sci 8:23–8. https://doi.org/10.4103/0975-7406.171699
Kakkar R, Kalra J, Mantha SV, Prasad K (1995) Lipid peroxidation and activity of antioxidant enzymes in diabetic rats. Mol Cell Biochem 151:113–119. https://doi.org/10.1007/bf01322333
Kayama Y, Raaz U, Jagger A, Adam M, Schellinger IN, Sakamoto M, Suzuki H, Toyama K, Spin JM, Tsao PS (2015) Diabetic cardiovascular disease induced by oxidative stress. Int J Mol Sci 16:25234–25263. https://doi.org/10.3390/ijms161025234
Khanra R, Dewanjee S, Dua TK, Sahu R, Gangopadhyay M, de Feo V, Zia-Ul-Haq M (2015) Abroma augusta L. (Malvaceae) leaf extract attenuates diabetes induced nephropathy and cardiomyopathy via inhibition of oxidative stress and inflammatory response. J Transl Med 13:6. https://doi.org/10.1186/s12967-014-0364-1
Kushiya F, Wada H, Ooi K, Sakurai Y, Sakaguchi A, Noda M, Abe Y, Nakasaki T, Tsukada T, Shiku H, Nobori T (2005) Effects of atorvastatin on serum lipids, lipoproteins, and hemostasis. Am J Hematol 78:1–6. https://doi.org/10.1002/ajh.20191
Larosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352:1425–1435. https://doi.org/10.1056/NEJMoa050461
Mayyas F, Alzoubi KH (2018) Cardiac effects of cigarette tobacco smoking in rat model of diabetes. Life Sci 211:279–285. https://doi.org/10.1016/j.lfs.2018.09.038
Mayyas F, Niebauer M, Zurick A, Barnard J, Gillinov AM, Chung MK, Vanwagoner DR (2010) Association of left atrial endothelin-1 with atrial rhythm, size and fibrosis in patients with structural heart disease. Circ Arrhythm Electrophysiol CIRCEP 3:369–79. https://doi.org/10.1161/CIRCEP.109.924985
Mayyas F, Alzoubi KH, Bonyan R (2017) The role of spironolactone on myocardial oxidative stress in rat model of streptozotocin-induced diabetes. Cardiovasc Ther 35(2). https://doi.org/10.1111/1755-5922.12242
Mayyas F, Baydoun D, Ibdah R, Ibrahim K (2018a) Atorvastatin reduces plasma inflammatory and oxidant biomarkers in patients with risk of atherosclerotic cardiovascular disease. J Cardiovasc Pharmacol Ther 23:216–225. https://doi.org/10.1177/1074248417753677
Mayyas F, Jaradat R, Alzoubi KH (2018b) Cardiac effects of fish oil in a rat model of streptozotocin-induced diabetes. Nutr Metab Cardiovasc Dis 28:592–599. https://doi.org/10.1016/j.numecd.2018.02.012
Mihaylova Z, Tsikandelova R, Sanimirov P, Gateva N, Mitev V, Ishkitiev N (2018) Role of PDGF-BB in proliferation, differentiation and maintaining stem cell properties of PDL cells in vitro. Arch Oral Biol 85:1–9. https://doi.org/10.1016/j.archoralbio.2017.09.019
Miller RG, Costacou T, Orchard TJ (2019) Risk factor modeling for cardiovascular disease in type 1 diabetes in the pittsburgh epidemiology of diabetes complications (EDC) study: a comparison with the diabetes control and complications trial/epidemiology of diabetes interventions and complications study (DCCT/EDIC). Diabetes 68:409–419. https://doi.org/10.2337/db18-0515
Olafsdottir E, Aspelund T, Sigurdsson G, Benediktsson R, Thorsson B, Harris TB, Launer LJ, Eiriksdottir G, Gudnason V (2013) Similar decline in mortality rate of older persons with and without type 2 diabetes between 1993 and 2004 the Icelandic population-based Reykjavik and AGES-Reykjavik cohort studies. BMC Public Health 13:36. https://doi.org/10.1186/1471-2458-13-36
Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424
Quidgley J, Cruz N, Crespo MJ (2014) Atorvastatin improves systolic function, but does not prevent the development of dilated cardiomyopathy in streptozotocin-induced diabetic rats. Ther Adv Cardiovasc Dis 8:133–144. https://doi.org/10.1177/1753944714531065
Ramesh B, Karuna R, Sreenivasa RS, Haritha K, Sai MD, Sasi BR, Saralakumari D (2012) Effect of Commiphora mukul gum resin on hepatic marker enzymes, lipid peroxidation and antioxidants status in pancreas and heart of streptozotocin induced diabetic rats. Asian Pac J Trop Biomed 2:895–900. https://doi.org/10.1016/s2221-1691(12)60249-4
Shen S, Wang F, Fernandez A, Hu W (2020) Role of platelet-derived growth factor in type II diabetes mellitus and its complications. Diab Vasc Dis Res 17:1479164120942119. https://doi.org/10.1177/1479164120942119
Taub PR, Gabbai-Saldate P, Maisel A (2010) Biomarkers of heart failure. Congest Heart Fail 16(Suppl 1):S19-24. https://doi.org/10.1111/j.1751-7133.2010.00168.x
Tolman KG, Fonseca V, Dalpiaz A, Tan MH (2007) Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 30:734–743. https://doi.org/10.2337/dc06-1539
Uttara B, Singh AV, Zamboni P, Mahajan R (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74
Widyantoro B, Emoto N, Nakayama K, Anggrahini DW, Adiarto S, Iwasa N, Yagi K, Miyagawa K, Rikitake Y, Suzuki T, Kisanuki YY, Yanagisawa M, Hirata K (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121:2407–2418. https://doi.org/10.1161/circulationaha.110.938217
Wiersma JJ, Meuwese MC, van Miert JN, Kastelein A, Tijssen JG, Piek JJ, Trip MD (2008) Diabetes mellitus type 2 is associated with higher levels of myeloperoxidase. Med Sci Monit 14:406–410
Yeboah J, Sane DC, Crouse JR, Herrington DM, Bowden DW (2007) Low plasma levels of FGF-2 and PDGF-BB are associated with cardiovascular events in type II diabetes mellitus (diabetes heart study). Dis Markers 23:173–178
Zeng H, Liu Z (2019) Atorvastatin induces hepatotoxicity in diabetic rats via oxidative stress, inflammation, and anti-apoptotic pathway. Med Sci Monit 25:6165–6173
Funding
This study was funded by the deanship of research (grant number 405/2021) at Jordan University of Science and Technology, Irbid, Jordan.
Author information
Authors and Affiliations
Contributions
Fadia Mayyas: conceptualization, software, validation, formal analysis, writing original draft, visualization, investigation, resources, project administration, and funding acquisition. Tala Algharram: methodology and data curation, resources, investigation, writing-review, and editing.
Corresponding author
Ethics declarations
Ethics approval
An approval from the Animal Care and Use Committee (ACUC) at Jordan University of Science and Technology (JUST) was obtained, approval number 16/4/12/455.
Consent to participate
Not applicable.
Consent for publications
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mayyas, F., Al Gharram, T. Impact of atorvastatin on plasma and cardiac biomarkers of inflammation, oxidative stress, and fibrosis in a rat model of streptozotocin-induced diabetes. Naunyn-Schmiedeberg's Arch Pharmacol 396, 261–274 (2023). https://doi.org/10.1007/s00210-022-02318-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-022-02318-z