Skip to main content
SpringerLink
Log in

Rosuvastatin alleviated the liver ischemia reperfusion injury by activating the expression of peroxisome proliferator-activated receptor gamma (PPARγ)

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Liver ischemia and reperfusion could cause serious damage to liver tissues. Abnormal liver function could induce serious damage and threaten human health. Evidence emerged to suggest that rosuvastatin could relieve cerebral ischemia–reperfusion injury and alleviate the disease related to vessels by activating the expression of PPARγ. However, whether rosuvastatin could relieve the liver ischemia reperfusion injury by enhancing the expression of PPARγ is unclear. For the strictness of experimental findings, we established both the rat models and the cell model of liver ischemia reperfusion injury by respectively treating rats and cells with rosuvastatin. PPARγ inhibitor was also used for the stimulation of these cells and rats. Reactive oxygen species (ROS) levels, apoptosis and related protein levels were determined with ROS staining, ROS staining and western blotting for the detection of injury induced by oxygen–glucose deprivation and re-oxygenation (OGD/R). Pretreatment of rosuvastatin promoted the expression of PPARγ in liver tissues and MIHA cells. It also inhibited the ischemia reperfusion and OGD/R induced production of ROS while promoted the release of SOD in liver tissues and MIHA cells. Furthermore, rosuvastatin also alleviated the ischemia reperfusion -induced apoptosis of liver tissues and OGD/R-induced MIHA cells apoptosis. However, application of PPARγ inhibitor abolished the restorative effects of rosuvastatin on the apoptosis and oxidative stress on liver tissues and MIHA cells. Rosuvastatin prevented the liver ischemia reperfusion injury of rats by activating PPARγ.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  • Chi X, Jiang Y, Chen Y, Yang F, Cai Q, Pan F, Lv L, Zhang X (2019) Suppression of microRNA-27a protects against liver ischemia/reperfusion injury by targeting PPARγ and inhibiting endoplasmic reticulum stress. Mol Med Rep 20:4003–4012

    CAS  PubMed  Google Scholar 

  • Choi IK, Kim YH, Kim JS, Seo JH (2008) PPAR-gamma ligand promotes the growth of APC-mutated HT-29 human colon cancer cells in vitro and in vivo. Investig New Drugs 26:283–288

    Article  CAS  Google Scholar 

  • Elshazly S, Soliman E (2019) PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. Toxicol Appl Pharmacol 362:86–94

    Article  CAS  Google Scholar 

  • Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M, Johnsson E, Zannad F (2009) Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360:1395–1407

    Article  Google Scholar 

  • Ferchichi H, Bacha S, Kourda N, Gaies E, Melaouhia S, Lakhal M, Klouz A, Trabelsi S, Salouage I (2016) Animal model of liver ischemia reperfusion: biochemical and histological evaluation. La Tunisie Medicale 94:235–243

    PubMed  Google Scholar 

  • Gong L, Wang X, Pan J, Zhang M, Liu D, Liu M, Li L, An F (2021) The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats. Open Med (wars) 15:47–57

    Google Scholar 

  • Heeba GH, Hamza AA (2015) Rosuvastatin ameliorates diabetes-induced reproductive damage via suppression of oxidative stress, inflammatory and apoptotic pathways in male rats. Life Sci 141:13–19

    Article  CAS  Google Scholar 

  • Herbet M, Izdebska M, Piątkowska-Chmiel I, Poleszak E, Jagiełło-Wójtowicz E (2016) Estimation of oxidative stress parameters in rats after simultaneous administration of rosuvastatin with antidepressants. Pharmacological Reports : PR 68:172–176

    Article  CAS  Google Scholar 

  • Huang Z, Zheng D, Pu J, Dai J, Zhang Y, Zhang W, Wu Z (2019) MicroRNA-125b protects liver from ischemia/reperfusion injury via inhibiting TRAF6 and NF-κB pathway. Biosci Biotechnol Biochem 83:829–835

    Article  CAS  Google Scholar 

  • Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H (1960) Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol 70:68–78

    CAS  PubMed  Google Scholar 

  • Jia P, Wu X, Pan T, Xu S, Hu J, Ding X (2019) Uncoupling protein 1 inhibits mitochondrial reactive oxygen species generation and alleviates acute kidney injury. EBioMedicine 49:331–340

    Article  Google Scholar 

  • Kanno M, Nakayama M, Zhu WJ, Hayashi Y, Kazama JJ (2018) Rosuvastatin pretreatment suppresses distant organ injury following unilateral renal ischemia-reperfusion in hypertensive Dahl salt-sensitive rats. Nephrology (carlton) 23:1046–1054

    Article  CAS  Google Scholar 

  • Katsumata Y, Shinmura K, Sugiura Y, Tohyama S, Matsuhashi T, Ito H, Yan X, Ito K, Yuasa S, Ieda M, Urade Y, Suematsu M, Fukuda K, Sano M (1979) Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2, Hypertension (Dallas. Tex 63(2014):80–87

    Google Scholar 

  • Li H, Xia Z, Chen Y, Qi D, Zheng H (2018) Mechanism and Therapies of Oxidative Stress-Mediated Cell Death in Ischemia Reperfusion Injury. Oxidative Med Cell Longevity 2018:2910643

    Google Scholar 

  • Li L, Wang S, Huang H, Cai Y, Xi Y, Bai Y, Ma C (2019) Effects of Rosuvastatin and Aspirin on Retinal Vascular Structures in Hypercholesterolemic Patients with Low-to-Moderate Risk of Coronary Artery Disease. Am J Cardiovasc Drugs 19:415–420

    Article  CAS  Google Scholar 

  • Linares I, Farrokhi K, Echeverri J, Kaths JM, Kollmann D, Hamar M, Urbanellis P, Ganesh S, Adeyi OA, Yip P, Selzner M, Selzner N (2018) PPAR-gamma activation is associated with reduced liver ischemia-reperfusion injury and altered tissue-resident macrophages polarization in a mouse model. PLoS One 13:e0195212

    Article  Google Scholar 

  • Liu YI, Liu Z, Chen Y, Xu K, Dong J (2016) PPARγ activation reduces ischemia/reperfusion-induced metastasis in a murine model of hepatocellular carcinoma. Exp Ther Med 11:387–396

    Article  Google Scholar 

  • Liu Y, Yang H, Jia G, Li L, Chen H, Bi J, Wang C (2018) The Synergistic Neuroprotective Effects of Combined Rosuvastatin and Resveratrol Pretreatment against Cerebral Ischemia/Reperfusion Injury. J Stroke Cerebrovasc Dis 27:1697–1704

    Article  Google Scholar 

  • Luo R, Sun X, Shen F, Hong B, Wang Z (2020) Effects of High-Dose Rosuvastatin on Ventricular Remodelling and Cardiac Function in ST-Segment Elevation Myocardial Infarction. Drug Des Devel Ther 14:3891–3898

    Article  CAS  Google Scholar 

  • Ma M, Uekawa K, Hasegawa Y, Nakagawa T, Katayama T, Sueta D, Toyama K, Kataoka K, Koibuchi N, Kuratsu J, Kim-Mitsuyama S (2013) Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation. Brain Res 1519:87–94

    Article  CAS  Google Scholar 

  • Nastos C, Kalimeris K, Papoutsidakis N, Tasoulis MK, Lykoudis PM, Theodoraki K, Nastou D, Smyrniotis V, Arkadopoulos N (2014) Global consequences of liver ischemia/reperfusion injury. Oxid Med Cell Longev 2014:906965

    Article  Google Scholar 

  • Orci LA, Lacotte S, Oldani G, Morel P, Mentha G, Toso C (2014) The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence. Digest Dis Sci 59:2058–2068

    Article  Google Scholar 

  • Osawa E, Nakajima A, Wada K, Ishimine S, Fujisawa N, Kawamori T, Matsuhashi N, Kadowaki T, Ochiai M, Sekihara H, Nakagama H (2003) Peroxisome proliferator-activated receptor gamma ligands suppress colon carcinogenesis induced by azoxymethane in mice. Gastroenterology 124:361–367

    Article  CAS  Google Scholar 

  • Patitucci C, Couchy G, Bagattin A, Cañeque T, de Reyniès A, Scoazec JY, Rodriguez R, Pontoglio M, Zucman-Rossi J, Pende M, Panasyuk G (2017) Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription. J Clin Invest 127:1873–1888

    Article  Google Scholar 

  • Pietrzykowski Ł, Michalski P, Kosobucka A, Kasprzak M, Fabiszak T, Stolarek W, Siller-Matula JM, Kubica A (2020) Medication adherence and its determinants in patients after myocardial infarction. Sci Rep 10:12028

    Article  CAS  Google Scholar 

  • Rani N, Arya DS (2020) Chrysin rescues rat myocardium from ischemia-reperfusion injury via PPAR-γ/Nrf2 activation. Eur J Pharmacol 883:173389

    Article  CAS  Google Scholar 

  • Ravingerova T, Adameova A, Carnicka S, Nemcekova M, Kelly T, Matejikova J, Galatou E, Barlaka E, Lazou A (2011) The role of PPAR in myocardial response to ischemia in normal and diseased heart. Gen Physiol Biophys 30:329–341

    Article  CAS  Google Scholar 

  • Saidi RF, Kenari SK (2014) Liver ischemia/reperfusion injury: an overview. J Invest Surg 27:366–379

    Article  Google Scholar 

  • Saleh H, El-Shorbagy HM (2020) Chitosan protects liver against ischemia-reperfusion injury via regulating Bcl-2/Bax TNF-α and TGF-β Expression. Int J Biol Macromol 164:1565–1574

    Article  CAS  Google Scholar 

  • Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM (1998) Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 4:1046–1052

    Article  CAS  Google Scholar 

  • Song ZC, Chen L, Zhang D, Zhang SY, Lin X (2018) Rosuvastatin protects acute myocardial infarction rats through autophagy regulation via AMPK signaling. Zhonghua Yi Xue Za Zhi 98:3536–3541

    CAS  PubMed  Google Scholar 

  • Takano S, Kubota T, Nishibori H, Hasegawa H, Ishii Y, Nitori N, Ochiai H, Okabayashi K, Kitagawa Y, Watanabe M, Kitajima M (2008) Pioglitazone, a ligand for peroxisome proliferator-activated receptor-gamma acts as an inhibitor of colon cancer liver metastasis. Anticancer Res 28:3593–3599

    CAS  PubMed  Google Scholar 

  • Wang L, Lin R, Guo L, Hong M (2018) Rosuvastatin relieves myocardial ischemia/reperfusion injury by upregulating PPAR-γ and UCP2. Mol Med Rep 18:789–798

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wei W, Peng J, Shen T (2019) Rosuvastatin Alleviates Ischemia/Reperfusion Injury in Cardiomyocytes by Downregulating Hsa-miR-24-3p to Target Upregulated Uncoupling Protein 2. Cell Reprogram 21:99–107

    Article  CAS  Google Scholar 

  • Wu Y, Tan X, Tian J, Liu X, Wang Y, Zhao H, Yan Z, Liu H, Ma X (2017) PPARγ Agonist Ameliorates the Impaired Fluidity of the Myocardial Cell Membrane and Cardiac Injury in Hypercholesterolemic Rats. Cardiovasc Toxicol 17:25–34

    Article  CAS  Google Scholar 

  • Xia P, Pan Y, Zhang F, Wang N, Wang E, Guo Q, Ye Z (2018) Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ. Cell Physiol Biochem 45:2351–2368

    Article  CAS  Google Scholar 

  • Zhang T, Shao B, Liu GA (2017) Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-γ. Eur Rev Med Pharmacol Sci 21:4464–4471

    CAS  PubMed  Google Scholar 

  • Zhang S, Feng Z, Gao W, Duan Y, Fan G, Geng X, Wu B, Li K, Liu K, Peng C (2020) Aucubin Attenuates Liver Ischemia-Reperfusion Injury by Inhibiting the HMGB1/TLR-4/NF-κB Signaling Pathway, Oxidative Stress, and Apoptosis. Front Pharmacol 11:544124

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, The First Hospital of Quanzhou Affiliated to Fujian Medical University, No. 250 East Street Licheng District, Quanzhou, 362000, Fujian, China

    Guiyuan Guo

  2. Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu Province, China

    Jie Cai

Authors
  1. Guiyuan Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jie Cai.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, G., Cai, J. Rosuvastatin alleviated the liver ischemia reperfusion injury by activating the expression of peroxisome proliferator-activated receptor gamma (PPARγ). J Bioenerg Biomembr 53, 573–583 (2021). https://doi.org/10.1007/s10863-021-09909-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-021-09909-0

Keywords

Search

Navigation