Abstract 10377: Constitutive Adiponectin Administration Using Adipocyte Sheet-Based Drug Delivery System Ameliorates Cardiac Dysfunction in Mouse Myocardial Infarction Model
Background: The adipocyte derived cytokine adiponectin (APN) has beneficial effects for cardiovascular diseases. However, APN targeted delivery to distressed myocardium in a constitutive manner is difficult. We investigated a novel drug delivery system based on tissue-engineered adipocyte sheets (AS) to supply APN in a constitutive manner and attenuate cardiac dysfunction in MI model mice.
Methods and Results: AS were created from adipose tissue-derived fibroblasts obtained from wild-type (WT) and APN knockout (KO) mice, which were cultured and differentiated into adipocytes in temperature-responsive culture dishes. After differentiation, AS secreted APN into culture supernatant (128.4±14.7 ng/day), whereas undifferentiated fibroblasts did not. To confirm APN secretion in vivo, fluorescent dye-labeled WT-AS were implanted into the LV anterior walls of KO mice. Immune-chemical analysis revealed that the AS survived on the epicardium and supplied APN to the extra-cellular matrix of the host myocardium implanted site for 1 month (Figure). AS-derived APN was also detected in plasma at 3 months after implantation (488.2±56.2 pg/ml). Fifteen minutes after LAD ligation, mice were divided into the WT-AS implantation (W), KO-AS implantation (K), and no treatment (C) groups. Two days after treatment, infarct size, TNFα expression, and macrophage infiltration were diminished in the W group as compared to the others. One month after implantation, cell diameter and percent fibrosis were lower, and fractional area change was significantly higher in the W (FAC: 48.9±4.1%; n=5), as compared to the K (33.0±3.5%; n=5; p<0.01 vs. W) and C (34.7±3.0%; n=5; p<0.02 vs. W) groups.
Conclusions: AS may provide constitutive APN locally and systematically, leading to reduced infarct size, inflammation suppression, and attenuation of LV remodeling and cardiac dysfunction in MI model mice. Tissue-engineered AS may be a promising drug delivery system for heart failure.
- © 2010 by American Heart Association, Inc.