Abstract P168: Activated Protein C Inhibits the Development of Myocardial Fibrosis

Background: Activated Protein C (aPC) is a naturally produced circulating anticoagulant with anti-inflammatory and cytoprotective properties proposed to have beneficial effects on the myocardium. Myocardial fibrosis is a pathophysiologic process evident in many cardiovascular diseases and is believed to directly contribute to eventual organ failure. Using a well-described model of myocardial fibrosis after Angiotensin II (AngII) infusion our aim was to investigate the novel therapeutic function of aPC in the development of fibrosis. Methods: C57Bl/6 mice were continuously infused with AngII (2.0 μ g/kg/min), AngII and aPC (0.4 μ g/kg/min), or saline for a 3d period. Hearts were harvested and processed for analysis. Cellular infiltration and collagen deposition were analyzed using histologic staining. Cellular apoptosis was assessed using a TUNEL assay. Quantitative RT-PCR was used to assess transcript levels of molecular mediators. Results: Infusion of AngII for 3d resulted in multifocal areas of myocardial cellular infiltration associated with significant collagen deposition compared to saline control animals (p≤0.01). The addition of aPC with AngII infusion inhibited this fibrotic response. Co-administration with aPC also inhibited the upregulation of the pro-fibrotic cytokine CTGF expression seen in AngII infused animals (p≤0.01). Apoptosis was also significantly inhibited when aPC was co-administered based on a decrease of in TUNEL positive cells and an increase expression ration of BCL/BAX suggesting an anti-apoptotic effect (p≤0.01), Furthermore, aPC also inhibited the up-regulation of the cell adhesion molecule p-selectin seen in AngII infused animals (p≤0.01). Conclusion: The co-administration of aPC in a model of myocardial fibrosis was able to abrogate completely the fibrotic response. The mechanism of action of aPC appears to be a decreased cellular adhesion molecule expression in the myocardium leading to decreased cellular infiltration and enhanced cellular survival. This data suggests that aPC has the potential as a therapeutic agent in cardiovascular diseases.