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Journal of Molecular Medicine

, Volume 96, Issue 12, pp 1345–1357 | Cite as

AdipoRon, an adiponectin receptor agonist, attenuates cardiac remodeling induced by pressure overload

  • Ning Zhang
  • Wen-Ying Wei
  • Hai-Han Liao
  • Zheng Yang
  • Can Hu
  • Sha-sha Wang
  • Wei DengEmail author
  • Qi-Zhu TangEmail author
Original Article

Abstract

AdipoRon, a small-molecule adiponectin receptor (AdipoR) agonist, has been reported to be implicated in cardiovascular diseases. However, its role in pressure-overload-induced cardiac remodeling is still elusive. To elucidate the role of AdipoRon in the pathogenesis of cardiac remodeling in vivo and vitro, in the left ventricle of human end-stage heart failure, the expression of AdipoR2 is upregulated. Meanwhile, increased expression of AdipoR2 was also observed in mice failing hearts. Oral administration of AdipoRon alleviated cardiac hypertrophy and fibrosis induced by pressure overload, as evidenced by the beneficial change of cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers, ventricle collagen ratio, and cardiac function. The AMPKα activation mediated by AdipoRon significantly inhibited AngII-induced TGF-β1 expression and cardiac fibroblast differentiation, and these inhibitory effects were abrogated by treatment with the AMPK inhibitor Compound C. Consistent with the above results, AdipoRon abolished the ability to retard AngII-induced TGF-β1 expression in AMPKα2−/− cardiac fibroblasts. In AMPKα2−/− mice subjected to aortic banding, AdipoRon abolished the protective effect, as indicated by increased cross-sectional area, cardiac collagen ratio, and cardiac dysfunction. Our results demonstrated that AdipoR2 expression was markedly increased in the failing hearts. AdipoRon inhibited TGF-β1 expression and myofibroblast differentiation in AMPKα-dependent manner in vitro. In line with the vitro results, AMPKα2−/− mice markedly abrogated the inhibitory effects of AdipoRon in cardiac remodeling. These results indicated AdipoRon may hold promise of an effective therapy against pressure-overload-induced cardiac remodeling.

Key messages

• The increased expression of AdipoR2 is observed in human and mice failing hearts, the changeable expression of AdipoR suggests the possible role of AdipoR in cardiac remodeling.

• Oral administration of AdipoRon alleviates cardiac hypertrophy and fibrosis induced by pressure overload, and AMPKα activation mediated by AdipoRon significantly inhibited AngII-induced TGF-β1 expression and cardiac fibroblast differentiation.

• These findings provide new mechanistic insight and open new therapeutic pathways for heart failure.

Keywords

AdipoRon Cardiac remodeling AMP-activated protein kinase TGF-β1 Myofibroblast differentiation 

Notes

Funding information

This study was supported by grants obtained from the Key Project of the National Natural Science Foundation (No. 81530012), the National Natural Science Foundation of China (No. 81470516, No.81270303), National Major Scientific Instrument and Equipment Development Projects (No. 2013YQ03092306), and The prevention and control project of cardiovascular disease (No.2016ZX-008-01).

Compliance with ethical standards

All the procedures and written informed consent were obtained from the families of the prospective heart donors. All the procedures complied with the principles of the Declaration of Helsinki and were approved by the Ethics Committee at the Renmin Hospital of Wuhan University in Wuhan, China.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

109_2018_1696_MOESM1_ESM.docx (1.3 mb)
ESM 1 (DOCX 1329 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ning Zhang
    • 1
    • 2
  • Wen-Ying Wei
    • 2
    • 3
    • 4
  • Hai-Han Liao
    • 2
    • 3
    • 4
  • Zheng Yang
    • 2
    • 3
  • Can Hu
    • 2
    • 3
  • Sha-sha Wang
    • 2
    • 3
  • Wei Deng
    • 2
    • 3
    Email author
  • Qi-Zhu Tang
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of CardiologyAffiliated Hospital of Qingdao UniversityQingdaoChina
  2. 2.Department of CardiologyRenmin Hospital of Wuhan UniversityWuhanPeople’s Republic of China
  3. 3.Cardiovascular Research Institute of Wuhan UniversityWuhanChina
  4. 4.Hubei Key Laboratory of CardiologyWuhanChina

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