부산대학교 도서관

Introduction:Refractory dilated cardiomyopathy has been reported to have pathophysiologies such as abnormalities in cytoskeletal protein, mitochondrial ATP transporter, microvasculature, and fibrosis, which may be main therapeutic target. The Mesenchymal stem cells (MSCs) have been already reported to have a potential to ameliorate the distressed mitochondria, structural protein, and anti-fibrotic effects by cytokine paracrine effect.Hypothesis:In this study we hypothesized that MSC transplantation may recover the cardiac function through regulation of mitochondrial function and cytoskeletal protein.Methods and Results:The adipose-derived MSC (ADSC) were implanted onto the cardiac surface of the delta sarcoglycan(SG)-deficient hamster 18 weeks after birth (A group, n=10)and sham operation was performed(C group, n=10).In the A group, left ventricular ejection fraction and end-systolic diameter were maintained during 4 weeks after transplantation (A vs. C group; EF 42.8 vs. 25.3%, p<0.05). The ATP concentration in the cardiomyocytes was significantly increased in A group (A vs. C group; 1.89 vs. 1.20 mol/mg weight tissue, p<0.05).In addition, expression of ANT-1, an ATP counter transporter located at mitochondrial inner membrane, significantly upregulated in the A group(A vs. C group; 65.02 vs. 21.49 %ANT-1/COX4 (vs. Normal), p<0.05).Histologically there were no significant differences in the expression of extra-cellular matrix and myocardial cytoskeletal proteins such as collagen, SG and ?-dystroglycan between groups. However, significant improvement of myosin and Smad-4 gene expression, the cardiomyocyte hypertrophy and capillary density were detected in the A group.In vitro, ELISA analysis revealed that the ADSC secreted cytokine such as HGF, VEGF and activin. From the above results, activin may act on the TGF-beta receptor on cardiomyocytes and Smad-4 related intracellular cascade may involve in the up-regulation of myosin.Conclusions:ADSC, which can deliver cytokines to distressed cardiomyocytes, may improve cardiac function in the DCM-like hamster with amelioration of ATP concentration, mitochondrial transporter and myosin expression, proposing possibilities in clinical application of ADSC therapy for DCM.