Skip to main content

Advertisement

SpringerLink
Log in

Irbesartan suppresses cardiac toxicity induced by doxorubicin via regulating the p38-MAPK/NF-κB and TGF-β1 pathways

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Doxorubicin (DOX) so far continues to be one of the most potent and effective anticancer drugs. Therefore, it is still needed to search for a safe and effective therapy that can opposite DOX-induced cardiotoxicity. Irbesartan (IRB), an angiotensin II receptor blocker, has a wide-ranging variety of biological activities. The present study was designed to explore the possible protective effects of IRB against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were divided into four groups: control, IRB (40 mg/kg, orally/daily) for 3 weeks, DOX (2.5 mg/kg, intraperitoneally/ three times weekly) for 2 weeks to obtain cumulative dose of 15 mg/kg, and finally IRB + DOX group. IRB inhibited cardiotoxicity induced by DOX which was evident by ECG changes, alterations of cardiac enzymes and histopathological changes. IRB improved DOX-induced alterations in oxidative/nitrosative status by decreasing lipid peroxidation and nitric oxide (NO) content in addition to increasing the antioxidant capacity. In addition, DOX triggers the cardiac expression of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB) where IRB diminished DOX-induced alterations in theses parameters. Moreover, DOX significantly increase the expression levels of caspase-3 and transforming growth factor-beta 1 (TGF-β1), while IRB exhibited anti-apoptotic and anti-fibrotic effects where it abolished these elevations. Meanwhile, DOX-induced activation of p38-mitogen activated protein kinase (p38-MAPK) which was inhibited by IRB. Collectively, these results proposed that IRB afforded a significant protection against DOX-induced cardiac damage by means of antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic remodeling mechanisms. These mechanisms are possibly mediated, at least in part, by alterations of TGF-β1/p38-MAPK/NF-κB signaling.

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

Similar content being viewed by others

Abbreviations

Ang-II:

Angiotensin II

ARBs:

Angiotensin receptor blockers

AT1R:

Angiotensin II type 1 receptor

CK-MB:

Creatine kinase MB

cTn-I:

Serum cardiac troponin-I

CVD:

Cardiovascular diseases

DOX:

Doxorubicin

ECG:

Electrocardiography

ELISA:

Enzyme-linked immunosorbent assay

GSH:

Reduced glutathione

H&E:

Hematoxylin and eosin

I/R:

Ischemia reperfusion

iNOS:

Inducible NO synthase

IRB:

Irbesartan

MDA:

Malondialdehyde

NF-κB:

Nuclear factor kappa B

NO:

Nitric oxide

p38-MAPK:

p38-Mitogen-activated protein kinase

PPAR-γ:

Peroxisome proliferator-activated receptor gamma

RAS:

Renin-angiotensin system

RHW:

Relative heart weight

ROS:

Reactive oxygen species

TAC:

Total antioxidant capacity

TBARS:

Thiobarbituric acid reactive substances

TGF-β1:

Transforming growth factor-beta 1

TNF-α:

Tumor necrosis factor-α

References

  • Abdel-Raheem IT, Omran GA, Katary MA (2015) Irbesartan an angiotensin II receptor antagonist, with selective PPAR-gamma-modulating activity improves function and structure of chemotherapy-damaged ovaries in rats. Fundam Clin Pharmacol 29:286–298

    Article  CAS  PubMed  Google Scholar 

  • Akolkar G, Bhullar N, Bews H, Shaikh B, Premecz S, Bordun KA, Cheung DY, Goyal V, Sharma AK, Garber P, Singal PK (2015) The role of renin angiotensin system antagonists in the prevention of doxorubicin and trastuzumab induced cardiotoxicity. Cardiovasc Ultrasound 13:18

    Article  PubMed  PubMed Central  Google Scholar 

  • American Cancer Society (2017) Cancer Facts and Figures. American Cancer Society, Atlanta

    Google Scholar 

  • Anjaneyulu M, Chopra K (2004) Effect of irbesartan on the antioxidant defence system and nitric oxide release in diabetic rat kidney. Am J Nephrol 24:488–496

    Article  CAS  PubMed  Google Scholar 

  • Arabacilar P, Marber M (2015) The case for inhibiting p38 mitogen-activated protein kinase in heart failure. Front Pharmacol 6:102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arafa MH, Mohammad NS, Atteia HH, Abd-Elaziz HR (2014) Protective effect of resveratrol against doxorubicin-induced cardiac toxicity and fibrosis in male experimental rats. J Physiol Biochem 70:701–711

    Article  CAS  PubMed  Google Scholar 

  • Bahadır A, Kurucu N, Kadıoğlu M, Yenilme E (2014) The role of nitric oxide in doxorubicin-induced cardiotoxicity: experimental study. Turk J Haematol 31:68–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banchroft JD, Stevens A, Turner DR (1996) Theory and practice of histological techniques, 4thEd. edn. ELsiver, Churchil Livingstone

    Google Scholar 

  • Berthiaume JM, Wallace KB (2007) Adriamycin-induced oxidative mitochondrial cardiotoxicity. Cell Biol Toxicol 23:15–25

    Article  CAS  PubMed  Google Scholar 

  • Cao Y, Ruan Y, Shen T, Huang X, Li M, Yu W, Zhu Y, Man Y, Wang S, Li J (2014) Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways. Oxidative Med Cell Longev 2014:1–12

    Article  CAS  Google Scholar 

  • Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS, Hagerty KL, Somerfield MR, Vaughn DJ (2007) ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 25:3991–4008

    Article  CAS  PubMed  Google Scholar 

  • Chen CT, Wang ZH, Hsu CC, Lin HH, Chen JH (2015) In vivo protective effects of diosgenin against doxorubicin-induced cardiotoxicity. Nutrients 7:4938–4954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng SM, Yang SP, Ho LJ, Tsao TP, Chang DM, Lai JH (2004) Irbesartan inhibits human T-lymphocyte activation through downregulation of activator protein-1. Br J Pharmacol 142:933–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Damiani RM, Moura DJ, Viau CM, Caceres RA, Henriques JAP, Saffi J (2016) Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch Toxicol 90:2063–2076

    Article  CAS  PubMed  Google Scholar 

  • Das J, Ghosh J, Manna P, Sil PC (2011) Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochem Pharmacol 81:891–909

    Article  CAS  PubMed  Google Scholar 

  • De Angelis A, Urbanek K, Cappetta D, Piegari E, Ciuffreda LP, Rivellino A, Russo R, Esposito G, Rossi F, Berrino L (2016) Doxorubicin cardiotoxicity and target cells: a broader perspective. Cardio-Oncol 2:2

    Article  Google Scholar 

  • Deng S, Kruger A, Schmidt A, Metzger A, Yan T, Gِdtel-Armbrust U, Hasenfuss G, Brunner F, Wojnowski L (2009) Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn Schmiedeberg's Arch Pharmacol 380:25–34

    Article  CAS  Google Scholar 

  • Dobrek T, Thor P (2013) Heart rate variability in overactive bladder experimental model. Arch Med Sci 9:930–935

    Article  PubMed  Google Scholar 

  • Elberry AA, Abd-Naim AB, Abdel-Sattar EA, Nagy AA, Mosli HA, Mohamadin AM, Ashour OS (2010) Cranberry (Vaccinium macrocarpon) protects against doxorubicin-induced cardiotoxicity in rats. Food Chem Toxicol 41:283–289

    Google Scholar 

  • Eschenhagen T, Force T, Ewer MS, De Keulenaer GW, Suter TM, Anker SD, Avkiran M, de Azambuja E, Balligand JL, Brutsaert DL, Condorelli G (2011) Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 13:1–10

    Article  PubMed  Google Scholar 

  • Fan Q, Liao J, Kobayashi M, Yamashita M, Gu L, Gohda T, Suzuki Y, Wang LN, Horikoshi S, Tomino Y (2004) Candesartan reduced advanced glycation end-products accumulation and diminished nitro-oxidative stress in type 2 diabetic KK/Ta mice. Nephrol Dial Transplant 19:3012–3020

    Article  CAS  PubMed  Google Scholar 

  • Gerhardt W, Waldenstrom J (1979) Creatine kinase B-subunit activity in serum after immunohinhibition of M-subunit activity. Clin Chem 25:1274–1280

    CAS  PubMed  Google Scholar 

  • Guo R, Wu K, Chen J, Mo L, Hua X, Zheng D, Chen P, Chen G, Xu W, Feng J (2013) Exogenous hydrogen sulfide protects against doxorubicin-induced inflammation and cytotoxicity by inhibiting p38MAPK/NFκB pathway in H9c2 cardiac cells. Cell Physiol Biochem 32:1668–1680

    Article  CAS  PubMed  Google Scholar 

  • Hadi NR, Al-Amran FG, Yousif MG, Zamil ST (2014) Irbesartan ameliorate inflammatory responses, and apoptosis induced by myocardial ischemia/reperfusion in male rats. Am J BioMed 2:608–624

    Google Scholar 

  • Han X, Zhou Y, Liu W (2017) Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. NPJ Precis Oncol 1:31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu B, Song JT, Ji XF, Liu ZQ, Cong ML, Liu DX (2017) Sodium ferulate protects against angiotensin IIinduced cardiac hypertrophy in mice by regulating the MAPK/ERK and JNK pathways. Biomed Res Int 2017:10. https://doi.org/10.1155/2017/3754942

  • Husain A, Azim MS, Mitra M, Bhasin PS (2011) A review of pharmacological and pharmaceutical profile of irbesartan. Pharmacophore 2:276–286

    CAS  Google Scholar 

  • Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR (2009) Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res 60:373–381

    Article  CAS  PubMed  Google Scholar 

  • Ibrahim MA, Amin EF, Ibrahim SA, Abdelzaher WY, Abdelrahman AM (2014) Montelukast and irbesartan ameliorate metabolic and hepatic disorders in fructose-induced metabolic syndrome in rats. Eur J Pharmacol 724:204–210

    Article  CAS  PubMed  Google Scholar 

  • Ikeda U, Maeda Y, Kawahara Y, Yokoyama M, Shimada K (1995) Angiotensin II augments cytokine-stimulated nitric oxide synthesis in rat cardiac myocytes. Circulation 92:2683–2689

    Article  CAS  PubMed  Google Scholar 

  • Jian CY, Ouyang HB, Xiang XH, Chen JL, Li YX, Zhou X, Wang JY, Yang Y, Zhong EY, Huang WH, Zhang HW (2017) Naringin protects myocardial cells from doxorubicin-induced apoptosis partially by inhibiting the p38MAPK pathway. Mol Med Rep 16:9457–9463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kataoka N, Nishida K, Kinoshita K, Sakamoto T, Nakatani Y, Tsujino Y, Mizumaki K, Inoue H, Kinugawa K (2016) Effect of irbesartan on development of atrial fibrosis and atrial fibrillation in a canine atrial tachycardia model with left ventricular dysfunction, association with p53. Heart Vessel 31:2053–2060

    Article  Google Scholar 

  • Kelleni MT, Amin EF, Abdelrahman AM (2015) Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in rats: impact of oxidative stress, inflammation, and apoptosis. J Toxicol 2015:1–8

    Article  CAS  Google Scholar 

  • Khafaga AF, El-Sayed YS (2018) All-trans-retinoic acid ameliorates doxorubicin-induced cardiotoxicity: in vivo potential involvement of oxidative stress, inflammation, and apoptosis via caspase-3 and p53 down-expression. Naunyn Schmiedeberg's Arch Pharmacol 391:59–70

    Article  CAS  Google Scholar 

  • Kim BH, Im Cho K, Kim SM, Kim JY, Choi BG, Kang JH, Jeon YK, Kim SS, Kim SJ, Kim YK, Kim IJ (2012) Irbesartan prevents myocardial remodeling in experimental thyrotoxic cardiomyopathy. Endocr J 59:919–929

    Article  CAS  PubMed  Google Scholar 

  • Kojda G, Harrison D (1999) Interaction between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 43:562–571

    Article  CAS  PubMed  Google Scholar 

  • Krishnamurthy B, Rani N, Bharti S, Golechha M, Bhatia J, Nag TC, Ray R, Arava S, Arya DS (2015) Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats. Chem Biol Interact 237:96–103

    Article  CAS  PubMed  Google Scholar 

  • Lemarié CA, Paradis P, Schiffrin EL (2008) New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. J Mol Med 86:673–678

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Liu Y, Fu Y, Wei T, Le Guyader L, Gao G, Liu RS, Chang YZ, Chen C (2012) The triggering of apoptosis in macrophages by pristine graphene through the MAPK and TGF-beta signaling pathways. Biomaterials 33:402–411

    Article  CAS  PubMed  Google Scholar 

  • Li C, Han R, Kang L, Wang J, Gao Y, Li Y, He J, Tian J (2017) Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis. Sci Rep 7:40523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu X, Xu Q, Wang X, Zhao Z, Zhang L, Zhong L, Li L, Kang W, Zhang Y, Ge Z (2015) Irbesartan ameliorates diabetic cardiomyopathy by regulating protein kinase D and ER stress activation in a type 2 diabetes rat model. Pharmacol Res 93:43–51

    Article  CAS  PubMed  Google Scholar 

  • Lou H, Danelisen I, Singal PK (2005) Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 288:H1925–H1930

    Article  CAS  PubMed  Google Scholar 

  • Ma S, Li X, Dong L, Zhu J, Zhang H, Jia Y (2016) Protective effect of Sheng-Mai Yin, a traditional Chinese prepartation, against doxorubicin- induced cardio toxicity in rats. BMC Complement Altern Med 16:1037–1039

    Google Scholar 

  • Maillet M, Van Berlo JH, Molkentin JD (2013) Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14:38–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marut W, Kavian N, Servettaz A, Hua-Huy T, Nicco C, Chéreau C, Weill B, Dinh-Xuan AT, Batteux F (2013) Amelioration of systemic fibrosis in mice by angiotensin II receptor blockade. Arthritis Rheum 65:1367–1377

    Article  CAS  PubMed  Google Scholar 

  • Mohamed EA, Ahmed HI, Zaky HS (2018) Protective effect of irbesartan against doxorubicin-induced nephrotoxicity in rats: implication of AMPK, PI3K/Akt, and mTOR signaling pathways. Can J Physiol Pharmacol 23(999):1–9

    Google Scholar 

  • Mukhopadhyay P, Rajesh M, Bátkai S, Kashiwaya Y, Haskó G, Liaudet L, Szabó C, Pacher P (2009) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol 296:H1466–H1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nade VS, Dharmadhikari PP, Kawale LA (2015) Anti-fibrotic effect of irbesartan via attenuation of endoplasmic reticulum stress in isoprenaline-induced myocardial fibrosis. Int J Pharmacol 4:76–82

    CAS  Google Scholar 

  • Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL (2012) Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 52:1213–1225

    Article  CAS  PubMed  Google Scholar 

  • Pai VB, Nahata MC (2000) Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 22:263–302

    Article  CAS  PubMed  Google Scholar 

  • Shoukry HS, Ammar HI, Rashed LA, Zikri MB, Shamaa AA, Abu-Al Rub E, Saravanan S, Dhingra S (2017) Prophylactic supplementation of resveratrol is more effective than its therapeutic use against doxorubicin induced cardiotoxicity. PLoS One 12:e0181535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Štěrba M, Popelová O, Vávrová A, Jirkovský E, Kovaříková P, Geršl V, Šimůnek T (2013) Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 18:899–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taguchi I, Toyoda S, Takano K, Arikawa T, Kikuchi M, Ogawa M, Abe S, Node K, Inoue T (2013) Irbesartan, an angiotensin receptor blocker, exhibits metabolic, anti-inflammatory and antioxidative effects in patients with high-risk hypertension. Hypertens Res 36:608–613

    Article  CAS  PubMed  Google Scholar 

  • Touyz RM, He G, El Mabrouk M, Diep Q, Mardigyan V, Schiffrin EL (2001) Differential activation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen activated-protein kinase by AT1 receptors in vascular smooth muscle cells from Wistar–Kyoto rats and spontaneously hypertensive rats. J Hypertens 19:553–559

    Article  CAS  PubMed  Google Scholar 

  • van Acker SA, Kramer K, Voest EE, Grimbergen JA, Zhang J, van der Vijgh WJ, Bast A (1996) Doxorubicin-induced cardiotoxicity monitored by ECG in freely moving mice. A new model to test potential protectors. Cancer Chemother Pharmacol 38:95–101

    Article  PubMed  Google Scholar 

  • Vignier N, Le Corvoisier P, Blard C, Sambin L, Azibani F, Schlossarek S, Delcayre C, Carrier L, Hittinger L, Su JB (2014) AT 1 blockade abolishes left ventricular hypertrophy in heterozygous c M y BP-C null mice: role of FHL 1. Fundam Clin Pharmacol 28:249–256

    Article  CAS  PubMed  Google Scholar 

  • Yang D, Yuan J, Liu G, Ling Z, Zeng H, Chen Y, Zhang Y, She Q, Zhou X (2013) Angiotensin receptor blockers and statins could alleviate atrial fibrosis via regulating platelet-derived growth factor/Rac1 /nuclear factor-kappa B axis. Int J Med Sci 10:812–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yousif NG, Hadi NR, Al-Amran F, Zigam QA (2018) Cardioprotective effects of irbesartan in polymicrobial sepsis. Herz 43:140–145

    Article  CAS  PubMed  Google Scholar 

  • Yu L, Hébert MC, Zhang YE (2002) TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J 21:3749–3759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao G, Zhao H, Tu L, Xu X, Zheng C, Jiang M, Wang P, Wang D (2010) Effects and mechanism of irbesartan on tubulointerstitial fibrosis in 5/6 nephrectomized rats. J Huazhong Univ Sci Technol Med Sci 30:48–54

    Article  CAS  PubMed  Google Scholar 

  • Zong WN, Yang XH, Chen XM, Huang HJ, Zheng HJ, Qin XY, Yong YH, Cao K, Huang J, Lu XZ (2011) Regulation of angiotensin-(1–7) and angiotensin II type 1 receptor by telmisartan and losartan in adriamycin-induced rat heart failure. Acta Pharmacol Sin 32:1345–1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, P.N. 11754, Egypt

    Nermin T. El-Said, Eman A. Mohamed & Ragia A. Taha

Authors
  1. Nermin T. El-Said
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eman A. Mohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ragia A. Taha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RA developed the research idea, performed and supervised the experiment execution and the data analysis, and revised the manuscript. EM designed the research idea and the experiments, performed and supervised the experiment execution, and wrote and revised the manuscript. NT performed the experiments, collected the data, and performed the graphical and statistical analysis.

Corresponding author

Correspondence to Eman A. Mohamed.

Ethics declarations

The study complies with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publications No. 8023, revised 1978) and is approved by the Ethics Committee of Faculty of Pharmacy, Al-Azhar University.

Conflict of interest

The authors declare that they have 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

El-Said, N.T., Mohamed, E.A. & Taha, R.A. Irbesartan suppresses cardiac toxicity induced by doxorubicin via regulating the p38-MAPK/NF-κB and TGF-β1 pathways. Naunyn-Schmiedeberg's Arch Pharmacol 392, 647–658 (2019). https://doi.org/10.1007/s00210-019-01624-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-019-01624-3

Keywords

Search

Navigation