Pharmacological blockade of αV integrin (CD51) reduces the development of pressure-overload-induced cardiac fibrosis

Abstract

Myocardial fibrosis is involved in most forms of heart diseases, progressively leading to adverse cardiac remodeling and heart failure. We previously identified a population of cardiac stromal cells that contribute to fibrosis development through a CD51 (alpha v integrin) dependent activation of pro-fibrotic pathways in a murine model of myocardial infarction. The pharmacological blockade of CD51 was associated with a significant reduction of fibrosis, preservation of cardiac function and improved survival. Investigate the impact of CD51 pharmacological blockers on the development of cardiac fibrosis induced by neurohormonal pro-hypertrophic stressors. We used C57Bl/6J mice infused with Angiotensin II (1.44 mg/kg/day) or dual Angiotensin II (1.44 mg/kg/day) + PhenylEphrine (50 mg/kg/day) through an osmotic pump for 28 or 14 days, respectively. Animals were treated with daily with intra-peritoneal injection of either CD51 blocker cilengitide or vehicle for the duration of the study. We found that both AngII and AngII + PE stimulation led to a similar cardiac hypertrophic remodeling: heart weight on body weight ratio as well as cardiomyocyte size were similarly increased. However, AngII + PE mice developed a significantly higher amount of interstitial fibrosis as compared to AngII mice (10.2 ± 4.3% vs. 4.5 ± 1.3% of total area respectively, P < 0.0001). Importantly, AngII + PE but not AngII mice exhibited a significant increase in CD51 expression and in the number of CD51+ cells as found in cytometry analysis. CD51 blockade significantly decreased the development of fibrosis under AngII + PE stimulation (7.6% ± 1.7, P < 0.05), as well as heart weight on body weight ratio (5.4 ± 0.5 vs. 5.7 ± 0.4, P < 0.05), but did not change the cardiomyocyte sizes. CD51 blockade also partially rescued the progressive drop in LVEF observed in mice stimulated with AngII + PE (47.5% ± 4.0 vs. 40.7% ± 13.8). Further cytometry analyses on cardiac tissues demonstrated that CD51 is expressed by stromal cells and by CCR2+ macrophages. Preliminary results indicate that the anti-fibrotic effects of CD51 blockade could come from a dual reduction on the activation of stromal and the immune-inflammatory response. Inhibition of CD51 reduces the development of cardiac fibrosis in response to pressure-overload, through the targeting of both stromal and inflammatory cardiac cells.