Table 1.

The CCL2/CCR2 axis in cardiac fibrosis

Experimental model of cardiac fibrosis	Findings	Cellular target and molecular mechanism	References
Transgenic CCL2 overexpression	Cardiomyocyte-specific CCL2 overexpression in mice induced myocardial inflammation and fibrotic changes.	Fibrogenic actions presumed due to inflammatory cell recruitment and activation.	124
Rat model of cardiovascular remodelling through chronic inhibition of NO synthesis	Treatment with anti-CCL2 antibody attenuated inflammation and reduced coronary vascular remodelling but did NOT affect fibrosis.	NA	125
Rat model of pressure overload through suprarenal aortic constriction	Anti-CCL2 antibody attenuated myocardial fibrosis.	Anti-fibrotic effects were presumed due to decreased macrophage recruitment and attenuated TGF-β release	126
Mouse model of non-reperfused myocardial infarction	Anti-CCL2 gene therapy attenuated interstitial fibrosis without affecting infarct size.	Anti-fibrotic effects were attributed to decreased macrophage infiltration and attenuated TNF-α and TGF-β levels.	127
Mouse model of reperfused myocardial infarction	CCL2 KO mice had attenuated myofibroblast proliferation and delayed granulation tissue formation after MI, associated with reduced dilative remodelling.	Anti-fibrotic effects were attributed to reduced macrophage recruitment and impaired macrophage activation, associated with markedly decreased expression of TGF-β and osteopontin.	128
Mouse model of ischaemic cardiomyopathy induced through brief repetitive ischaemia/reperfusion	CCL2 KO mice had attenuated interstitial fibrosis, associated with reduced macrophage recruitment and decreased fibroblast proliferation.	CCL2 did not have direct effects on proliferation or expression of fibrosis-associated genes by cardiac fibroblasts. Thus, the profibrotic effects of CCL2 were attributed to actions on macrophages.	129
Mouse model of angiotensin II-induced fibrosis	CCL2 KO mice had attenuated fibrosis.	Fibrogenic effects of CCL2 were attributed to recruitment of circulating fibroblast precursors. This notion was based on the presence of CD34+/CD45+ collagen-expressing fibroblast-like cells in the myocardium.	50
Mouse model of angiotensin II-induced fibrosis	CCR2 KO mice had attenuated angiotensin II-mediated cardiac fibrosis.	Fibrogenic effects of CCR2 were attributed to recruitment of bone marrow-derived fibroblast precursors. This notion was based on the presence of CD34+/CD45+ collagen-expressing fibroblast-like cells in the myocardium.	130
Mouse model of angiotensin II-induced fibrosis	CCR2 KO mice had attenuated angiotensin II-mediated cardiac fibrosis.	Fibrogenic effects of CCR2 were attributed to attenuated recruitment of fibroblast progenitors. This notion was based on detection of CD45/α-SMA+ cells. CCR2-mediated fibrosis was attributed to actions of CCL12 (and not CCL2), based on associative data.	131
Mouse model of mineralocorticoid receptor-mediated cardiac fibrosis	In a deoxycorticosterone (DOC)/salt model, CCL2 KO mice had 35% less myocardial fibrosis.	Fibrogenic effects of CCL2 were attributed to actions on macrophage recruitment and activation. However, CCL2 KO mice also had lower blood pressure, suggesting that the fibrogenic actions of CCL2 may be indirect, reflecting effects on blood pressure regulation.	132
Mouse model of ageing	Aged CCL2 KO mice had reduced fibrosis and attenuated diastolic dysfunction.	Attenuated fibrosis in CCL2 KO mice was associated with reduced leucocyte infiltration.	133
Mouse model of angiotensin-induced fibrosis	Administration of a CCR2 antagonist attenuated myocardial inflammation and fibrosis.	CCL2 up-regulation was stimulated by angiotensin-induced CaMKIIδ activation. The mechanisms for the fibrogenic effects of the CCL2/CCR2 axis were not investigated.	134
Mouse model of left ventricular pressure overload	Depletion of CCR2+ monocytes ameliorated cardiac fibrosis.	The findings highlighted the role of the monocytes recruited through CC chemokines in the pathogenesis of myocardial fibrosis.	135
Mouse model of streptozotocin-induced diabetes	Diabetic CCR2 KO mice had attenuated myocardial fibrosis.	The fibrogenic actions were attributed to macrophage-driven inflammation and oxidative stress.	136