Abstract P149: Mozobil Increases Myocardial Fibrosis via the Recruitment of Fibrocytes in the Angiotensin II--Treated Heart
Background: Fibroblast progenitor cells (fibrocytes) are important to the development of myocardial fibrosis and suggested to migrate to the chemokine CXCL12. CXCL12 has one primary receptor, CXCR4, to which the inhibitor Mozobil competitively binds. Mozobil has been shown to inhibit recruitment of fibrocytes to the lungs following bleomycin injury, but its affects on progenitor cells in the heart remains unclear. We hypothesized that if CXCL12 is necessary for fibrocyte recruitment, Mozobil would inhibit fibrocyte infiltration into the myocardium and consequently, decrease fibrosis.
Methods: C57/Bl6 mice were treated with saline (control), AngII, or AngII+Mozobil via osmotic mini-pump. Mice were sacrificed at day 3 and tissues were collected for RNA, protein and histology. Heart sections were stained with H&E and Sirius Red and analyzed for cellular infiltrate and collagen deposition, respectively. Infiltrate was measured using standardized grid counts on a single heart section. The percent area affected was the number of grids containing cellular infiltrate over the total grids containing heart tissue (∼375 grids per section). Fibrocytes were cultured from mouse peripheral blood following mobilization with Mozobil. Fibrocytes were stained for collagen-1, CD133 and CXCR4.
Results: Cultured fibrocytes were positive for markers CD133 and collagen-1, as well as CXCR4. AngII infusion resulted in significant cellular infiltration, affecting 30.0 ± 4.0% (n=8) of the myocardium, relative to saline (0.3% ± 0.4; n=8). In contrast, animals receiving AngII+Mozobil had 78.9±3.1% (n=5) of the myocardium affected (p<0.05). Increased infiltrate was also associated with significantly increased collagen deposition: Control (4.3% ± 0.1), AngII (11.9% ± 1.9), and AngII+Mozobil (29.0% ± 4.8). Furthermore, the infiltrate was positive for the progenitor marker CD133.
Conclusion: Our findings confirm isolated fibrocytes express CXCR4. Unexpectedly however, our findings suggest CXCL12 is not required for the migration of fibrocytes to the myocardium, based on the failure of CXCR4 blockade to limit migration. Our findings suggest that increased migration into the heart may be through the increased mobilization of progenitor cells from the bone marrow.
- © 2011 by American Heart Association, Inc.