Abstract
AimsMyocardial fibrosis contributes to the development of heart failure. Activated Protein C (aPC) is a circulating anticoagulant with anti-inflammatory and cytoprotective properties. Using a model of myocardial fibrosis second to Angiotensin II (AngII) infusion, we investigated the novel therapeutic function aPC in the development of fibrosis.Methods and ResultsC57Bl/6 and Tie2-EPCR mice were infused with AngII (2.0 µg/kg/min), AngII and aPC (0.4 µg/kg/min) or saline for 3d. Hearts were harvested and processed for analysis or used for cellular isolation. Basic histology and collagen deposition were assessed using histologic stains. Transcript levels of molecular mediators were analyzed by quantitative RT-PCR. Mice infused with AngII exhibited multifocal areas of myocardial cellular infiltration associated with significant collagen deposition compared to saline control animals (p<0.01). AngII-aPC infusion inhibited this cellular infiltration and the corresponding collagen deposition. AngII-aPC infusion also inhibited significant expression of the pro-fibrotic cytokines TGF-β1, CTGF and PDGF found in AngII only infused animals (p<0.05). aPC signals through its receptor, EPCR. Using Tie2-EPCR animals, where endothelial cells over-express EPCR and exhibit enhanced aPC-EPCR signaling, no significant reduction in cellular infiltration or fibrosis was evident with AngII infusion suggesting aPC-mediate protection is endothelial cell independent. Isolated infiltrating cells expressed significant EPCR transcripts suggesting a direct effect on infiltrating cells.ConclusionsThis data indicates that aPC treatment abrogates the fibrogenic response to AngII. aPC does not appear to confer protection by stimulating the endothelium but by acting directly on the infiltrating cells, potentially inhibiting migration or activation.
Highlights
Myocardial fibrosis is a common sequelae associated with many cardiovascular diseases and is characterized by the accumulation of excess extracellular (ECM) proteins within the myocardial tissues [1]
This data indicates that Activated Protein C (aPC) treatment abrogates the fibrogenic response to Angiotensin II (AngII). aPC does not appear to confer protection by stimulating the endothelium but by acting directly on the infiltrating cells, potentially inhibiting migration or activation
Hemodynamic Measurements To assess the impact of aPC treatment in a model of myocardial fibrosis secondary to AngII infusion, we assigned animals to four experimental groups
Summary
Myocardial fibrosis is a common sequelae associated with many cardiovascular diseases and is characterized by the accumulation of excess extracellular (ECM) proteins within the myocardial tissues [1]. Fibrocytes are capable of producing both pro-inflammatory mediators and fibrogenic factors[3,5,6] They are believed to be capable of bridging an initial inflammatory response to a later corresponding fibrotic response [7,8]. Fibrocyte infiltration is followed by a loss of functional myocytes and an accumulation of extracellular matrix proteins within the myocardial tissue resulting in the development of myocardial fibrosis [3,4,6]
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