CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction

Zamilpa R, Kanakia R, Cigarroa J IV, Dai Q, Escobar GP, Martinez H, Jimenez F, Ahuja SS, Lindsey ML. CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 300: H1418-H1426, 2011. First published February 4, 2011; doi:10.1152/ajpheart.01002.2010.-Post-myocardial infarction (MI), chemokine homing of inflammatory cells into the injured left ventricle (LV) regulates ventricular remodeling, in part by stimulating the extracellular matrix 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. Accordingly, we examined LV function, macrophage recruitment and activation, and collagen content in wild-type (WT, n = 25) and CCR5 null (n = 33) mice at 7 days post-MI. Both groups had similar infarct sizes (44 +/- 2% in WT and 42 +/- 2% in CCR5 null; P = 0.37). However, the LV remodeling index (end diastolic volume/LV mass) increased to a larger extent in CCR5 null (1.28 +/- 0.08 mu l/mg for CCR5 null and 1.02 +/- 0.06 mu l/mg for WT; P < 0.05). Although numbers of infiltrated macrophages were similar in WT and CCR5 null mice, CCR5-deficient macrophages isolated from the infarct zone displayed >50% decrease in gene expression levels of proinflammatory activation markers (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-beta 1) compared with WT (all P < 0.05). Concomitant with the reduced macrophage activation, heat shock protein-47 and collagen type I precursor levels in the infarct region decreased in the CCR5 null (1.2 +/- 0.3 units in the CCR5 null and 2.3 +/- 0.4 units in the WT; P < 0.05), while collagen fragments increased (88.3 +/- 5.9 units in the CCR5 null and 32.7 +/- 8.5 units in the WT; P < 0.05). We conclude that CCR5 deletion impairs LV remodeling by hindering macrophage activation, which stimulates an imbalance in collagen metabolism and increases the remodeling index.