Table 1.

Experimental studies investigating the role of the CCL2/CCR2 axis in heart failure

Heart failure model	Intervention	Effects on cardiac function and remodeling	Cellular target and molecular mechanism	Reference
Rat model of pressure overload through suprarenal aortic constriction	Anti-CCL2 neutralizing antibody	Anti-CCL2 antibody ameliorated diastolic dysfunction.	Decreased macrophage recruitment, fibroblast proliferation and TGF-β production associated with attenuated myocardial fibrosis	[120]
Mouse model of left ventricular pressure overload	CCR2 antagonist and antibody-mediated CCR2+ cell depletion	CCR2 antagonist and depletion of CCR2+ cells attenuated LV dilation and systolic dysfunction	Attenuated CCR2+ macrophage recruitment, cardiomyocyte hypertrophy, and cardiac fibrosis	[123]
Mouse model of non-reperfused myocardial infarction	Anti-CCL2 gene therapy	Anti-CCL2 therapy attenuated LV dilatation and systolic dysfunction, and increased post-MI survival	Attenuated interstitial fibrosis, macrophage infiltration, and TNF-α and TGF-β1 levels	[124]
Mouse model of reperfused myocardial infarction	CCL2 KO and antibody neutralization	CCL2 KO mice had reduced post-infarction dilative remodeling	Attenuated myofibroblast proliferation, reduced macrophage recruitment and activation, associated with reduced fibrosis and delayed granulation tissue formation	[19]
Mouse model of ischemic cardiomyopathy induced through brief repetitive ischemia/reperfusion	CCL2 KO and antibody neutralization	CCL2 KO mice had improved systolic function, evidenced by increased fractional shortening	Reduced fibroblast proliferation and macrophage recruitment associated with attenuated interstitial fibrosis	[17]
Mouse model of ischemia/reperfusion	Depletion of CCR2+ macrophages (by injecting DT in CCR2-DTR mice)	Depletion of CCR2+ macrophages improved LV systolic function, and reduced LV dilation	Reduced infarct size and attenuated cardiomyocyte hypertrophy	[125]
Mouse model of angiotensin II-induced cardiac remodeling	CCL2 KO	CCL2 loss did not affect systolic function, but attenuated fibrosis	Attenuated fibrogenic effects of Ang-II, and the expression of TNF-α and TGF-β1	[126]
Mouse model of aging	CCL2 KO	Aged CCL2 KO mice had attenuated diastolic dysfunction	Reduced leukocyte infiltration, associated with attenuated fibrosis	[127]
Mouse model of streptozotocin-induced diabetes	CCR2 KO CCR2 inhibitor	CCR2 KO and inhibitor improved cardiac function and reduced LV dilation in diabetic mice	Attenuated cardiomyocyte apoptosis and induced polarization of M2 macrophages. In addition, CCR2 KO reduced myocardial fibrosis presumably due to decreased macrophage-driven inflammation and oxidative stress	[128]
N/A	Transgenic Cardiomyocyte-specific CCL2 overexpression	Cardiomyocyte-specific CCL2 overexpression in mice induced cardiac hypertrophy and dilation	Induced myocardial inflammation and fibrotic changes attributed to inflammatory cell recruitment and activation	[129]

KO knockout