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. 2004 Aug;165(2):439-47.
doi: 10.1016/S0002-9440(10)63309-3.

Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction

Koichi Kaikita  1 , Takanori Hayasaki, Toshiyuki Okuma, William A Kuziel, Hisao Ogawa, Motohiro Takeya
Affiliations

Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction

Koichi Kaikita et al. Am J Pathol. 2004 Aug.

Abstract

A key component of cardiac remodeling after acute myocardial infarction (MI) is the inflammatory response, which modulates cardiac tissue repair. The purpose of this study was to investigate the relationship between the monocytic inflammatory response and left ventricular remodeling after MI using mice deficient in CC chemokine receptor 2 (CCR2), the primary receptor for the critical regulator of CC chemokine ligand 2. Immunohistochemical analysis revealed rapid infiltration of macrophages into infarcted tissue within 7 days in wild-type (WT) mice. However, this process was greatly impaired in CCR2-deficient (CCR2(-/-)) mice. Echocardiography demonstrated beneficial effects of CCR2 deficiency on left ventricular remodeling at 7 and 28 days after MI. In situ zymography showed augmented gelatinolytic activity in WT mice within 7 days after MI, whereas gelatinolytic activity was barely detectable in CCR2(-/-) mice. Moreover, the distribution of gelatinolytic activity in serial sections was very similar to the distribution of macrophages rather than neutrophils. Expression of matrix metalloproteinases and tumor necrosis factor-alpha mRNAs was up-regulated in infarcted regions from WT mice compared to CCR2(-/-) mice at 3 days after MI. Direct inhibition of CCR2 functional pathway might contribute to the attenuation of left ventricular remodeling after MI.

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Figures

Figure 1
Figure 1
A: Representative examples of Masson’s trichrome and van Gieson staining at 7 days after experimental MI. Stained slides demonstrate that necrotic centers of infarcted regions remain devoid of fibrosis in CCR2−/− mice, with less accumulation of collagen in CCR2−/− mice than in WT mice. B and C: Infarct size (B) and infarct area (C) in WT and CCR2−/− mice. D: Collagen volume fraction from van Gieson-stained myocardium as a percentage of stained tissue in muscle areas and connective tissue in visual fields of the sections. *, P < 0.01 versus CCR2−/− mice.
Figure 2
Figure 2
Immunohistochemical detection of FA-11-positive macrophages in infarcted regions from WT (left) and CCR2−/− (right) mice at 1, 3, 7, 14, and 28 days after experimental MI. Scale bars, 100 μm.
Figure 3
Figure 3
Differences in numbers of FA-11-positive macrophages (A), Gr-1-positive granulocytes (B), B220-positive B cells (C), and Ly-1-positive T cells (D) in infarcted regions from WT and CCR2−/− mice. Data points represent the number of positive cells per 1 mm2 in infarcted tissues. *, P < 0.01 versus CCR2−/− mice. †, P < 0.05 versus WT mice.
Figure 4
Figure 4
Serial changes in LVDD (A) and %FS (B) in sham-operated (n = 6, each group) and MI (n = 14, each group) WT and CCR2−/− mice. *, P < 0.01 versus CCR2−/− MI group.
Figure 5
Figure 5
A: In situ zymography and immunohistochemistry using monoclonal antibodies for CD68 (FA-11) or granulocytes (Gr-1) in serial sections of infarcted myocardium from WT (left) and CCR2−/− mice (right). Lysis of gelatin in contact with the proteolytic areas of the sections is indicated by negative staining on the slides. To distinguish MMP activity from the activity of other proteinases in the tissue, gelatin films containing 1,10-phenanthroline as an MMP inhibitor (indicated as MMP+I in the figures) are used. B: Morphometric analysis of the gelatinolytic area/infarct area at 1, 3, 7, 14, and 28 days after experimental MI in WT and CCR2−/− mice. *, P < 0.01 versus CCR2−/− mice. Scale bars, 500 μm.
Figure 6
Figure 6
Real-time RT-PCR results for MMP-8 (A), MMP-9 (B), MMP-13 (C), TIMP-1 (D), TIMP-4 (E), and TNF-α (F) mRNA levels in infarcted (I), noninfarcted (NI), and sham-operated (S) myocardium from WT and CCR2−/− mice at 3 days after MI. Relative quantitation values of these mRNA levels were normalized with respect to endogenous control 18S ribosomal RNA gene expression. *, P < 0.01 versus the other group. †, P < 0.05 versus the other group.
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