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Inhibition of Angiotensin II-Induced Cardiac Fibrosis by Atorvastatin in Adiponectin Knockout Mice

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  • Published:
Lipids

An Erratum to this article was published on 13 October 2017

This article has been updated

Abstract

Adiponectin is a polypeptide known to inhibit cardiac fibrosis via the activation of ‎adenosine monophosphate-activated protein kinase (AMPK). Statins can also activate AMPK, resulting in the secretion of adiponectin. We determined whether atorvastatin inhibits angiotensin II-induced cardiac fibrosis (AICF) in the presence or absence of adiponectin. Adiponectin knockout (APN-KO, n = 44) and wild type (WT, n = 44) mice were received subcutaneous angiotensin II (1.5 mg/kg/day), and atorvastatin (10 mg/kg/day) was administered orally for 15 days. The mRNA expression levels of collagen type I and III, as well as AMPK phosphorylation levels in cardiac tissue were then measured. In the APN-KO mice, collagen type I (p < 0.001) and type III (p = 0.001) expression was significantly greater when treated with angiotensin II, while their expression was significantly reduced in the presence of angiotensin II and atorvastatin. Relative AMPK phosphorylation levels in APN-KO mice were also significantly higher in the angiotensin II + atorvastatin group when compared with angiotensin II group alone. We conclude that atorvastatin attenuates AICF independently from adiponectin by activating AMPK. These data suggest potential cardioprotection beyond lipid modulation potentially supporting statin pleiotropic hypothesis.

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Change history

  • 13 October 2017

    In the original published article, Victor Serebruany was designated as the corresponding author in error. The corresponding author is Jong Sung Park. Dr. Park can be reached by email at thinkmed@dau.ac.kr.

Abbreviations

AMPK:

Adenosine monophosphate-activated protein kinase

ATP:

Adenosine triphosphate

APN-KO:

Adiponectin knockout

AICF:

Angiotensin II-induced cardiac fibrosis

BW:

Body weight

ERK:

Extracellular signal-regulated kinase

HW:

Heart weight

TGF:

Transforming growth factor

References

  1. Beauloye C, Bertrand L, Horman S, Hue L (2011) AMPK activation, a preventive therapeutic target in the transition from cardiac injury to heart failure. Cardiovasc Res 90(2):224–233

    Article  CAS  PubMed  Google Scholar 

  2. Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785

    Article  CAS  PubMed  Google Scholar 

  3. Zhang P, Hu X, Xu X, Fassett J, Zhu G, Viollet B, Xu W, Wiczer B, Bernlohr DA, Bache RJ, Chen Y (2008) AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension 52(5):918–924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Du J, Guan T, Zhang H, Xia Y, Liu F, Zhang Y (2008) Inhibitory crosstalk between ERK and AMPK in the growth and proliferation of cardiac fibroblasts. Biochem Biophys Res Commun 368(2):402–407

    Article  CAS  PubMed  Google Scholar 

  5. Stuck BJ, Lenski M, Böhm M, Laufs U (2008) Metabolic switch and hypertrophy of cardiomyocytes following treatment with angiotensin II are prevented by AMP-activated protein kinase. J Biol Chem 283(47):32562–32569

    Article  CAS  PubMed  Google Scholar 

  6. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8(11):1288–1295

    Article  CAS  PubMed  Google Scholar 

  7. Xu A, Vanhoutte PM (2012) Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Am J Physiol Heart Circ Physiol 302(6):H1231–H1240

    Article  CAS  PubMed  Google Scholar 

  8. Fujita K, Maeda N, Sonoda M, Ohashi K, Hibuse T, Nishizawa H, Nishida M, Hiuge A, Kurata A, Kihara S, Shimomura I, Funahashi T (2008) Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-alpha. Arterioscler Thromb Vasc Biol 28(5):863–870

    Article  CAS  PubMed  Google Scholar 

  9. Konishi M, Haraguchi G, Ohigashi H, Ishihara T, Saito K, Nakano Y, Isobe M (2011) Adiponectin protects against doxorubicin-induced cardiomyopathyby anti-apoptotic effects through AMPK up-regulation. Cardiovasc Res 89(2):309–319

    Article  CAS  PubMed  Google Scholar 

  10. Zhou Q, Liao JK (2010) Pleiotropic effects of statins-Basic research and clinical perspectives. Circ J 74(5):818–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yamamoto C, Fukuda N, Jumabay M, Saito K, Matsumoto T, Ueno T, Soma M, Matsumoto K, Shimosawa T (2011) Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with Ang II and high salt loading. Hypertens Res 34(3):348–353

    Article  CAS  PubMed  Google Scholar 

  12. An Z, Yang G, He YQ, Dong N, Ge LL, Li SM, Zhang WQ (2013) Atorvastatin reduces myocardial fibrosis in a rat model with post-myocardial infarction heart failure by increasing the matrix metalloproteinase-2/tissue matrix metalloproteinase inhibitor-2 ratio. Chin Med J (Engl) 126(11):2149–2156

    CAS  Google Scholar 

  13. Rodrigues Díez R, Rodrigues-Díez RR, Lavoz C, Rayego-Mateos S, Civantos E, Rodríguez-Vita J, Mezzano S, Ortiz A, Egido J, Ruiz-Ortega M (2010) Statins inhibit angiotensin II/Smad pathway and related vascular fibrosis, by a TGF-β-independent process. PLoS One 5(11):e14145

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rupérez M, Rodrigues-Díez R, Blanco-Colio LM, Sánchez-López E, Rodríguez-Vita J, Esteban V, Carvajal G, Plaza JJ, Egido J, Ruiz-Ortega M (2007) HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways. Hypertension 50(2):377–383

    Article  PubMed  Google Scholar 

  15. Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y, Shyy JY (2006) Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation 114(24):2655–2662

    Article  CAS  PubMed  Google Scholar 

  16. Hermida N, Markl A, Hamelet J, Van Assche T, Vanderper A, Herijgers P, van Bilsen M, Hilfiker-Kleiner D, Noppe G, Beauloye C, Horman S, Balligand JL (2013) HMG CoA reductase inhibition reverses myocardial fibrosis and diastolic dysfunction through AMP-activated protein kinase activation in a mouse model of metabolic syndrome. Cardiovasc Res 99(1):44–54

    Article  CAS  PubMed  Google Scholar 

  17. Qu HY, Xiao YW, Jiang GH, Wang ZY, Zhang Y, Zhang M (2009) Effect of atorvastatin versus rosuvastatin on levels of serum lipids, inflammatory markers and adiponectin in patients with hypercholesterolemia. Pharm Res 26(4):958–964

    Article  CAS  PubMed  Google Scholar 

  18. Blanco-Colio L, Martín-Ventura JL, Gómez-Guerrero C, Masramon X, de Teresa E, Farsang C, Gaw A, Gensini G, Leiter LA, Langer A, Egido J (2008) Adiponectin plasma levels are increased by atorvastatin treatment in subjects at high cardiovascular risk. Eur J Pharmacol 586(1–3):259–265

    Article  CAS  PubMed  Google Scholar 

  19. Sugiyama S, Fukushima H, Kugiyama K, Maruyoshi H, Kojima S, Funahashi T, Sakamoto T, Horibata Y, Watanabe K, Koga H, Sugamura K, Otsuka F, Shimomura I, Ogawa H (2007) Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease. Atherosclerosis 194(2):e43–e51

    Article  CAS  PubMed  Google Scholar 

  20. Inami N, Nomura S, Shouzu A, Omoto S, Kimura Y, Takahashi N, Tanaka A, Nanba M, Shouda Y, Iwasaka T (2007) Effects of pitavastatin on adiponectin in patients with hyperlipidemia. Pathophysiol Haemost Thromb 36(1):1–8

    Article  CAS  PubMed  Google Scholar 

  21. Essick EE, Ouchi N, Wilson RM, Ohashi K, Ghobrial J, Shibata R, Pimentel DR, Sam F (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301(3):H984–H993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, Loibner H, Wang XH, Penninger JM, Kassiri Z, Oudit GY (2010) Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction. Circulation 122(7):717–728

    Article  CAS  PubMed  Google Scholar 

  23. Zadelaar S, Kleemann R, Verschuren L, de der Vries-Van Weij J, van der Hoom J, Princen HM, Kooistra T (2007) Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol 27(8):1706–1721

    Article  CAS  PubMed  Google Scholar 

  24. Nie P, Li D, Hu L, Jin S, Yu Y, Cai Z, Shao Q, Shen J, Yi J, Xiao H, Shen L, He B (2014) Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors. PLoS One 9(5):e97009

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hunyady L, Catt KJ (2006) Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol 20(5):953–970

    Article  CAS  PubMed  Google Scholar 

  26. Serebruany VL, Miller M, Pokov AN, Malinin AI, Lowry DR, Tanguay JF, Hennekens CH (2006) Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study). Am J Cardiol 97(9):1332–1336

    Article  CAS  PubMed  Google Scholar 

  27. Han SH, Quon MJ, Kim JA, Koh KK (2007) Adiponectin and cardiovascular disease: response to therapeutic interventions. J Am Coll Cardiol 49(5):531–538

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors declare no conflicts of interest. Part of this work was supported by the “Brain Pool” program funded by the Korea Ministry of Science and Technology to Dr. Serebruany.

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Authors and Affiliations

  1. Department of Biomedical Laboratory Science, Daegu Health College, Daegu, Republic of Korea

    Sun Young Choi

  2. Department of Cardiology, College of Medicine, Dong-A University, Busan, Republic of Korea

    Jong Sung Park & Moo Hyun Kim

  3. Department of Pathology, College of Medicine, Dong-A University, Busan, Republic of Korea

    Mee Sook Roh

  4. Department of Biomedical Laboratory Science, College of Biomedical Sciences and Engineering, Inje University, Gimhae, Republic of Korea

    Chong-Rak Kim

  5. HeartDrug™ Research Laboratories, Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, MD, 21204, USA

    Victor Serebruany

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  1. Sun Young Choi
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Correspondence to Victor Serebruany.

Additional information

An erratum to this article is available at https://doi.org/10.1007/s11745-017-4296-4.

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Choi, S.Y., Park, J.S., Roh, M.S. et al. Inhibition of Angiotensin II-Induced Cardiac Fibrosis by Atorvastatin in Adiponectin Knockout Mice. Lipids 52, 415–422 (2017). https://doi.org/10.1007/s11745-017-4246-1

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  • DOI: https://doi.org/10.1007/s11745-017-4246-1

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