Adiponectin ameliorates iron-overload cardiomyopathy through the PPARα-PGC-1-dependent signaling pathway

Heng Lin, Wei Shiung Lian, Hsi Hsien Chen, Pei Fang Lai, Ching Feng Cheng

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Adiponectin is a circulating adipose-derived cytokine that may act as an antioxidative and anti-inflammatory protein. Although adiponectin has been reported to exert cytoprotective effects in acute cardiac diseases, its effects on chronic heart failure are less clear. Therefore, we aimed to investigate whether adiponectin would have a beneficial effect in iron-induced chronic heart failure and to elucidate its regulation in cardiomyocytes. Mice were first treated with iron dextran for 4 weeks to induce iron-overload cardiomyopathy. They exhibited decreased survival with impaired left ventricle contractility and decreased serum adiponectin levels. In vivo cardiac adiponectin gene (ADIPOQ) overexpression with adenoassociated virus (AAV)-ADIPOQ ameliorated cardiac iron deposition and restored cardiac function in iron-overloaded mice. In addition, AAV-ADIPOQ-treated iron-overload mice had lower expression of inflammatory markers, including myeloperoxidase activity, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-6, and intercellular adhesion molecule-1, than iron-overloaded mice not treated with AAV-ADIPOQ. Our in vitro study showed that adiponectin induced heme oxygenase-1 (HO-1) expression through the peroxisome proliferator-activated receptor (PPAR)α- HO-1 signaling pathway. Furthermore, the adiponectin-mediated beneficial effects were PPARα-dependent as the adiponectin-mediated attenuation of iron deposition was abolished in PPARα-knockout mice. Finally, PPARα-HO-1 signaling involved PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) binding and nuclear translocation, and their levels were increased by adiponectin therapy. Together, these findings suggest that adiponectin acts as an anti-inflammatory signaling molecule and induces the expression of HO-1 through the PPARα-PGC-1 complex-dependent pathway in cardiomyocytes, resulting in the attenuation of iron-induced cardiomyopathy. Using adiponectin for adjuvant therapies in iron-overload cardiac dysfunction may be an option in the future.

Original languageEnglish
Pages (from-to)275-285
Number of pages11
JournalMolecular Pharmacology
Volume84
Issue number2
DOIs
Publication statusPublished - Aug 2013

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Peroxisome Proliferator-Activated Receptors
Iron Overload
Adiponectin
Cardiomyopathies
Iron
Heme Oxygenase-1
Viruses
Cardiac Myocytes
Anti-Inflammatory Agents
Heart Failure
Chemokine CCL2
Acute Disease
Intercellular Adhesion Molecule-1
Dextrans
Knockout Mice
Peroxidase
Heart Ventricles
Heart Diseases
Interleukin-6
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Adiponectin ameliorates iron-overload cardiomyopathy through the PPARα-PGC-1-dependent signaling pathway. / Lin, Heng; Lian, Wei Shiung; Chen, Hsi Hsien; Lai, Pei Fang; Cheng, Ching Feng.

In: Molecular Pharmacology, Vol. 84, No. 2, 08.2013, p. 275-285.

Research output: Contribution to journalArticle

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