Effect of Adiponectin on Cardiac Allograft Vasculopathy

• Published in: Circulation Journal 2011, Vol.75(8), pp.2005-2012
• Main Authors: Ishihara, Takashi, Haraguchi, Go, Konishi, Masanori, Ohigashi, Hirokazu, Saito, Kiyomi, Nakano, Yasuko, Isobe, Mitsuaki
• Format: Article
• Language: English
• Subjects: Adiponectin; Adiponectin - genetics; Adiponectin - metabolism; Adiponectin - pharmacology; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Cardiac transplantation; Cell Proliferation - drug effects; Chronic Disease; Coronary Vessels - metabolism; Coronary Vessels - pathology; Graft Rejection - genetics; Graft Rejection - metabolism; Graft Rejection - pathology; Heart Transplantation; Hyperplasia; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Lymphocyte Activation - drug effects; Lymphocyte Activation - genetics; Mice; Mice, Transgenic; Myocytes, Smooth Muscle - metabolism; Neointima - genetics; Neointima - metabolism; Neointima - pathology; Protein Kinase Inhibitors - pharmacology; Receptors, Adiponectin - biosynthesis; Receptors, Adiponectin - genetics; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transplantation, Homologous
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-10-0879

Background: The role of adiponectin (APN), an adipose tissue-specific secretory protein, on chronic rejection after cardiac transplantation in APN-sense transgenic mice (APN-SE) was evaluated. Methods and Results: Heterotopic cardiac transplantation in major histocompatibility complex class II-mismatched mice was performed. B6.C-H-2bm12KhEg (Bm12) hearts were transplanted into APN-SE, and allografts were harvested at 8 weeks after transplantation. Quantitative polymerase chain reaction (PCR) and immunohistochemical staining showed that the expression of both AdipoR1 and AdipoR2 was induced in APN-SE recipients. Neointimal hyperplasia was significantly decreased in allografts transplanted into APN-SE (luminal occlusion, 8.9±2.2%) compared to those transplanted into controls (49.4±10.5%; P=0.011). APN-SE showed significantly reduced mRNA levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, and monocyte chemoattractant protein-1 (MCP-1) by quantitative PCR. Western blot analysis revealed that the protein levels of IFN-γ and MCP-1 were reduced in APN-SE recipients. Proliferation of smooth muscle cells stimulated with activated T cells was suppressed by APN addition, and this effect was canceled by treatment with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. Conclusions: APN plays a critical role in the attenuation of chronic rejection by suppressing inflammatory cytokine and chemokine expression and enhancing APN receptor expression. APN plays a beneficial role in reducing the progression of cardiac allograft vasculopathy through the AMPK pathway. (Circ J 2011; 75: 2005-2012)