Abstract 18401: CC Chemokine Receptor 5 Deletion Prevents Macrophage Activation and Collagen Turnover Following Myocardial Infarction
Post-myocardial infarction (MI), chemokine homing of inflammatory cells into injured myocardium regulates ventricular remodeling, in part by stimulating the extracellular matrix (ECM) response. The CC Chemokine Receptor 5 (CCR5) is a key chemokine receptor expressed on macrophages, and CCR5 ligands are highly upregulated post-MI. We hypothesized that deletion of CCR5 would attenuate adverse remodeling by decreasing inflammatory cell recruitment. Surprisingly, CCR5 Null (Null) mice had a 75% mortality rate, compared to 37% in wild-type (WT) mice over the 28 days post-MI period. Because Null mice showed peak increases in end diastolic dimensions by day 7 post-MI, we examined left ventricular (LV) function, macrophage recruitment and activation, and collagen content in WT (n=25) and Null (n=33) mice at 7 days post-MI. Both groups had similar infarct sizes (44±2% in WT and 42±2% in Null; p=0.37). However, the LV remodeling index (end diastolic volume / LV mass) increased to a larger extent in the Null compared with WT (1.28±0.08 μl/mg and 1.02±0.06 μl/mg, respectively; p<0.05). Although numbers of infiltrated macrophages were similar in Null and WT mice, CCR5 deficient macrophages isolated from the infarct zone had a greater than 50% decrease in gene expression levels of pro-inflammatory markers (IL-1β, IL-6, and TNF-α) as well as anti-inflammatory markers (Arginase 1, CD163, mannose receptor, and TGFβ1) compared to WT (all p<0.05). Concomitant with the reduced macrophage activation, collagen type I precursor levels decreased (1.2±0.3 units in the Null and 2.3±0.4 units in the WT; p<0.05) while collagen degradation increased (88.3±5.9 units in the Null and 32.7±8.5 units in the WT; p<0.05) LV infarcts post-MI. We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates excessive collagen degradation and increases the remodeling index.
- © 2010 by American Heart Association, Inc.