CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts.
The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 has potent mononuclear cell chemo-attractant properties, modulates fibroblast and endothelial cell phenotype and may play an important role in wound healing. In order to examine whether MCP-1 critically regulates myocardial infarct healing, we studied the effects of MCP-1 gene disruption and antibody neutralization in a closed-chest model of reperfused murine myocardial infarction. MCP-1-/- mice had decreased and delayed macrophage infiltration in the healing infarct and demonstrated delayed replacement of injured cardiomyocytes with granulation tissue. In contrast, the time course and density of neutrophil infiltration was similar in MCP-1 null and wild-type animals. MCP-1-/- infarcts had decreased mRNA expression of the cytokines TNF-alpha, IL-1beta, TGF-beta2, -beta3, and IL-10 and demonstrated defective macrophage differentiation evidenced by decreased Osteopontin-1 expression. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis. Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1-/- mice had attenuated left ventricular remodeling, but similar infarct size when compared with wild-type animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1-/- animals without an effect on macrophage recruitment. MCP-1 has important effects on macrophage recruitment and activation, cytokine synthesis and myofibroblast accumulation in healing infarcts. Absence of MCP-1 results in attenuated post-infarction left ventricular remodeling, at the expense of a prolonged inflammatory phase and delayed replacement of injured cardiomyocytes with granulation tissue.
Dewald
Oliver
O
Section of Cardiovascular Sciences, DeBakey Heart Center, Baylor College of Medicine, and the Methodist Hospital, Houston, Tex 77030, USA.
Zymek
Pawel
P
Winkelmann
Kim
K
Koerting
Anna
A
Ren
Guofeng
G
Abou-Khamis
Tareq
T
Michael
Lloyd H
LH
Rollins
Barrett J
BJ
Entman
Mark L
ML
Frangogiannis
Nikolaos G
NG
D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology*; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006099:Granuloma / Q000473:pathology; D007962:Leukocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000032:analysis; D020257:Ventricular Remodeling
D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin