Adiponectin Ameliorates Iron-Overload Cardiomyopathy through the PPARa–PGC-1–Dependent Signaling Pathway

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, AAVADIPOQ–treated iron-overload mice had lower expression of inflammatory markers, including myeloperoxidase activity, monocyte chemotactic protein-1, tumor necrosis factor-a, 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)a– HO-1 signaling pathway. Furthermore, the adiponectin-mediated beneficial effects were PPARa-dependent as the adiponectinmediated attenuation of iron deposition was abolished in PPARa-knockout mice. Finally, PPARa–HO-1 signaling involved PPARa 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 antiinflammatory signaling molecule and induces the expression of HO-1 through the PPARa–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.