Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently.
OBJECTIVE
CCR2, the receptor for monocyte chemoattractant protein 1 (MCP1), is involved in atherosclerosis and abdominal aortic aneurysms (AAAs). Here, we explored the potential beneficial blockade of the MCP1/CCR2 pathway.


METHODS
We applied an AAA model in aging apolipoprotein E deficient mice with pre-existing atherosclerotic lesions. These mice were subjected to two therapeutic strategies. First, a dominant negative form of MCP1 was overexpressed in femoral muscles, resulting in circulating levels of MCP1-7ND (7ND), competing with native MCP1. In the second approach, bone marrow transplantation was performed using bone marrow cells that were infected with a lentiviral construct containing siRNA for CCR2, to specifically inhibit only leukocyte CCR2 expression.


RESULTS
Both strategies did not influence lesion size of the advanced atherosclerotic plaques. However, 7ND induced a more fibrous plaque phenotype. Yet, surprisingly a trend in increased number and severity of AAA was observed in the 7ND group. Smooth muscle cells in the aneurysm showed decreased phosphorylated signal transducer and activator of transcription five (STAT5, P<0.01) in the 7ND group, which is indicative for a decreased proliferative and migratory (wound healing) response. This presumably resulted in the increased AAA development. In contrast, siRNA-induced inhibition of CCR2 in leukocytes led to a significant inhibition in aneurysm formation. In conclusion, systemic inhibition of the MCP1/CCR2 pathway leads to a fibrous plaque phenotype in the advanced atherosclerotic lesions, but to potential adverse effects on AAA formation, implying that for a beneficial overall therapeutic approach, specific inhibitory targeting of leukocyte CCR2 will be essential.
de Waard
Vivian
V
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands. v.dewaard@amc.uva.nl
Bot
Ilze
I
de Jager
Saskia C A
SC
Talib
Sara
S
Egashira
Kensuke
K
de Vries
Margreet R
MR
Quax
Paul H A
PH
Biessen
Erik A L
EA
van Berkel
Theo J C
TJ
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors*; D007962:Leukocytes / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D001057:Apolipoproteins E; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; D054390:Receptors, CCR2; D050799:STAT5 Transcription Factor