A6251 Periostin splicing variant regulates cardiac fibrosis after myocardial infarction

Abstract

Objectives: Although mortality rate due to acute myocardial infarction (AMI) has been extremely improved by the development of early reperfusion therapy, chronic heart failure following AMI is still clinically major issue. We previously demonstrated the level of periostin increased significantly following ischemia. Periostin alternative splicing variant 1 (Pn 1) over-expression resulted in ventricular dilation with enhanced interstitial collagen deposition in rat AMI model. However, the role of alternative splicing variants of periostin is still unclear. Methods: We employed neutralizing antibody (PnAb) that selectively inhibit Pn 1 by blockade of exon-17 and tested in rat AMI model by injecting once a week (200ug ip) throughout experiments. Results: Administration of PnAb resulted in a significant decrease in infarcted and fibrotic area of myocardium preventing ventricular wall thinning and dilatation. Moreover, surviving myocytes in ischemic area was significantly larger than that of control IgG group. Inhibition of fibrosis by PnAb was associated with a significant decrease in gene expression of fibrotic markers such as collagen I, collagen III, and TGF-β1. Importantly, the number of α-SMA positive myofibroblasts was significantly reduced in the heart treated with PnAb, while cardiomyocyte proliferation and angiogenesis were comparable in both IgG and PnAb group. Additionally, the level of Pn 1 expression was correlated significantly with the severity of AMI. In vitro study revealed that Pn 1, but not Pn 2 or 4, inhibited fibroblast and myocyte attachment, leading to myocyte death which might account for cell slippage observed during cardiac remodeling. Conclusion: Specific inhibition of Pn exon-17 by neutralizing antibody without suppressing other Pn variants might offer a new class of medication for the