Targeted Deletion of CC Chemokine Receptor 2 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction

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.

β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

“…Data are expressed as mean ± SEM. Further, in our current study, we did not observe an altered progression toward heart failure in CCR2KO BMT mice, which, coupled with the positive outcome of CCR2 inhibition in the aforementioned studies (25,26) versus the catastrophic impact of immune cell-specific β2AR deletion on cardiac remodeling following MI we previously reported (7), suggests that β2ARKO chimeric mice likely have additional factors that contribute to their observed post-MI phenotype. For instance, we previously showed that enhanced vascular cell adhesion molecule 1 expression was associated with splenic retention of leukocytes in β2ARKO BMT mice and that splenectomy partially restored cardiac leukocyte infiltration following MI (7), demonstrating that even with diminished CCR2 expression and responsiveness, β2AR-deficient leukocytes retain some capacity to traffic to sites of injury in vivo.…”

“…These discrepancies may be a result of the timing of administration or inhibition, because short-term elevations in CCL2 are protective whereas sustained elevations in CCL2 contribute to an enhanced progression toward heart failure (21)(22)(23)(24). Indeed, studies examining the involvement of CCR2 following cardiac injury have shown beneficial effects with CCR2 inhibition (25)(26)(27), wherein both global and monocyte-directed RNAi-mediated deletion of CCR2 in mice that underwent MI surgery resulted in improved left ventricular remodeling (25,26). CCR2 is highly expressed on proinflammatory monocyte populations and, although β2AR has been shown to modulate chemotaxis, our findings are novel in that they directly link decreased hematopoietic cell β2AR expression with a corresponding reduction in CCR2 levels and CCL2-dependent migration.…”

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

“…Markedly increased thrombus collagen was observed in the CCR2 Ϫ/Ϫ mice at early time points and at 4 days was associated with reduced vein wall levels of MMP-2 and MMP-9, suggesting impaired collagenolysis. This observation has also been described in a model of pulmonary and cardiac fibrosis in CCR2 Ϫ/Ϫ mice, showing significantly reduced MMP-2 and MMP-9 activity (11,47). Although MMP-9 has collagenolytic activity, it is primarily against type I collagen, for which little was present in the thrombus.…”

Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart

“…The observations that macrophage depletion results in delayed cardiac repair and worsened outcomes after MI (3), whereas inhibition of monocyte recruitment to the heart improves outcomes after MI (22), have long been viewed as contradictory. In light of our recent understanding of macrophages ontology, it may now be possible to reconcile these seemingly contradictory findings.…”