Abstract 18802: Endothelial-Mesenchymal Transition (EndMT) of the Atrial Endocardial Endothelial Layer: A Potential Contributor to Atrial Pathological Remodeling?
Introduction: Atrial fibrosis is a major contributor to the atrial fibrillation substrate but the mechanisms underlying its formation remain poorly understood. One major molecule implicated in enhanced fibrosis in response to atrial stress is Angiotensin II. EndMT describes the process of endothelial cell (EC) transformation into a myofibroblast - the major extracellular matrix synthesizing cell.
Methods & Results: Atria of 4-6 week old angiotensin converting enzyme overexpressing mice (ACE88) were compared to ACE wild-types (WT). qPCR demonstrated significantly increased Col1A2 (11.5+/-0.7vs2.7+/-0.7; p=7.3E-6) and FN1 (2.7+/-0.1vs0.86+/-0.16 ; p=7.3E-6) transcripts in ACE88 compared to WT. Interestingly, collagen I & CD31 immunolabeling revealed a more complex transmural fibrotic pattern: intra-atrial collagen I was increased as expected, but a strong increase in collagen I intensity was also detected in the endothelial layer enveloping atrial fascicles and lining the endocardial free wall. CD31 immunolabeling of ACE88 atria revealed a “rugged” lining of atria endocardial free-walls & fascicles compared to the finely demarcated WT counterparts. Significantly increased intra-atrial uptake of Evan’s Blue dye in ACE88 vs WT (0.15+/-0.01vs 0.04+/-0.006; p=<0.002) confirmed a disruption of endothelial barrier function. In addition, atria of 16-week old mice with myocardial infarction (MI) were studied at 2 & 4 weeks postMI. Similar to ACE88 mice, mRNAs for Col1A2 (0.91+/-0.1vs1.5+/-0.2 ; p=0.06) and FN1 (0.9+/-0.2vs1.3+/-0.1; p=0.052) showed a strong tendency for upregulation 4 weeks post-MI compared to aged-matched c57 atria (c57). Surprisingly, strongest collagen I post-MI labeling localized in proximity to CD31 labeling at 2 weeks, with little change in intra-atrial collagen I content. Significantly increased collagen I intensity was detected in the endocardial EC layer 4 weeks post-MI compared to c57 (31+/- 3vs45+/-3; p=0.009).
Conclusions: These data suggest the endocardial EC layer may be an early sensor to increased atrial stress; endocardial EndMT may be an early event during the atrial remodeling process and perhaps contributes to global intra-atrial remodeling through altered paracrine and/or permeability mechanisms.
- © 2013 by American Heart Association, Inc.