title: CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction.
abstract: 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 μl/mg for CCR5 null and 1.02 ± 0.06 μl/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-1β, interleukin-6, and tumor necrosis factor-α), as well as anti-inflammatory activation markers (arginase 1, CD163, mannose receptor, and transforming growth factor-β1) 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.
authors.affiliation: Division of Geriatrics, Gerontology and Palliative Medicine, Department of Medicine, The University of Texas Health Science Center at San Antonio, USA.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Zamilpa
authors.forename: Rushit
authors.initials: R
authors.lastname: Kanakia
authors.forename: Joaquin
authors.initials: J
authors.lastname: Cigarroa
authors.forename: Qiuxia
authors.initials: Q
authors.lastname: Dai
authors.forename: G Patricia
authors.initials: GP
authors.lastname: Escobar
authors.forename: Hernan
authors.initials: H
authors.lastname: Martinez
authors.forename: Fabio
authors.initials: F
authors.lastname: Jimenez
authors.forename: Seema S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D001119:Arginase / Q000096:biosynthesis; D024042:Collagen Type I / Q000096:biosynthesis; D005260:Female; D017353:Gene Deletion; D050958:HSP47 Heat-Shock Proteins / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000096:biosynthesis; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology; D011347:Procollagen / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000235:genetics* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D024042:Collagen Type I; D050958:HSP47 Heat-Shock Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011347:Procollagen; D019713:Receptors, CCR5; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C544448:Arg1 protein, mouse; D001119:Arginase