Losartan inhibits monocytic adhesion induced by ADMA via downregulation of chemokine receptors in monocytes.
OBJECTIVE
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, can induce the adhesiveness of monocytes to vascular endothelium, and chemokines play an important role in this process. The present study was carried out to test whether the inhibitory effect of losartan on ADMA-induced monocytic adhesion is mediated by chemokine receptors.


METHODS
Human monocytoid cells (THP-1) were incubated with exogenous ADMA (30 microM) for 4 or 24 h in the absence or presence of losartan. The monocytic adhesion, the levels of chemokines, and the expression of chemokine receptors were determined. The possible signal pathway was also explored.


RESULTS
In cultured monocytes, ADMA (30 microM) markedly increased monocytic adhesion to endothelial cells, elevated the levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and upregulated the mRNA expression of chemokine receptors CCR2 and CXCR2. Exposure to ADMA (30 microM) significantly induced the generation of intracellular reactive oxygen species (ROS) and activation of nuclear factor (NF)-kappaB. Pretreatment with AT1 receptor blocker (ARB) losartan (1, 3, 10 microM) attenuated monocytic adhesiveness elicited by ADMA and downregulated the expression of CCR2 and CXCR2 mRNA, accompanied by a significant decrease in ROS generation and NF-kappaB activity and expression.


CONCLUSIONS
The present study suggests that the inhibitory effect of losartan on ADMA-induced monocytic adhesion may be related to downregulation of chemokine receptors by inhibiting the ROS/NF-kappaB pathway.
Chen
Mei-Fang
MF
Department of Geriatric Medicine, Xiang-Ya Hospital, Central South University, Xiang-Ya Road #141, Changsha, Hunan 410008, People's Republic of China.
Li
Yuan-Jian
YJ
Yang
Tian-Lun
TL
Lou
Bin
B
Xie
Xiu-Mei
XM
D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D019808:Losartan / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D018932:Chemokine CCL2; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C018524:N,N-dimethylarginine; D001120:Arginine; D019808:Losartan