Abstract 15201: A Novel Prostacyclin Agonist, Ono1301®, Improves the Cardiac Function Through Reverse Cytoskeletal Protein in Dilated Cardiomyopathic Hamster; a Promising Regenerative Therapy for Failing Heart
Background: Aberrations in cytoskeletal proteins of myocyte have been suggested to play an important role in progression of left ventricular (LV) remodeling in dilated cardiomyopathy (DCM). ONO1301®, a synthetic prostacyclin agonist, has been shown to upregulate a variety of cardioprotective factors related to cytoskeletal protein structure. We thus hypothesized that ONO1301® may reverse LV remodeling through several mechanisms including reversed cytoskeletal proteins in DCM.
Methods and Results: Expression of hepatic growth factor, vascular endothelial growth factor, stromal cell-derived factor-1 and granulocyte colony stimulating factor was up-regulated in normal human dermal fibroblast and human coronary smooth muscle cell by adding ONO1301® in a dose-dependent manner in vitro, assessed by real-time PCR. J2N-K hamsters, which is the δ-sarcoglycan-deficient DCM model, were treated by epicardial implantation of atelocollagen sheet with or without ONO1301® elution (n=22 each), or sham operation (n=23). Survival period was significantly prolonged post-ONO1301® treatment compared to that post-collagen only (P=0.02) or the post-sham (P=0.03). Both diastolic and systolic dimensions of the LV were significantly smaller 1 month after the ONO1301® implantation (5.2±0.1 and 3.6±0.2 mm, respectively) than those after the atelocollagen only (5.6±0.2 and 4.1±0.1 mm, respectively) or the sham (5.7±0.1 and 4.2±0.1 mm, respectively), assessed by echocardiography. These findings were consistent to collagen accumulation and capillary density in the myocardial interstitium. Importantly, expression of α-dystroglycan, α- and β-sarcoglycan was significantly and markedly greater following ONO1301® treatment compared to those following the atelocollagen only or the sham, assessed by immunohistolabeling.
Conclusion: ONO1301® reorganized sarcoglycan and dystroglycan, increased capillaries and reduced fibrosis with functional benefits, suggesting its contribution to regenerate damaged myocardium in DCM hamster
- © 2011 by American Heart Association, Inc.