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

Rogelio Zamilpa, Rushit Kanakia, Joaquin Cigarroa, Qiuxia Dai, G. Patricia Escobar, Hernan Martinez, Fabio Jimenez, Seema S. Ahuja, Merry L. Lindsey

Research output: Contribution to journalArticle

41 Scopus citations

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- β 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.

Original languageEnglish (US)
Pages (from-to)H1418-H1426
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number4
DOIs
StatePublished - Apr 1 2011

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Keywords

  • CC chemokines
  • Inflammation
  • Matrix metalloproteinases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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