Inhibition of chemokine receptor CCR2 and CCR5 expression contributes to simvastatin-induced attenuation of cardiac allograft vasculopathy.
BACKGROUND
Accumulating evidence reveals that statins possess pleiotropic properties beyond cholesterol reduction, which may contribute to the attenuation of cardiac allograft vasculopathy (CAV). Recent in vitro data suggest that statins could down-regulate chemokine receptors. This study was designed to test the hypothesis that simvastatin ameliorates CAV development via the inhibition of chemokine receptor expression in an inbred rat model of cardiac transplantation.


METHODS
Animals were divided into four groups: isograft; control (cyclosporine [CsA] + vehicle); low-dose simvastatin (LSIM; CsA + 5 mg/kg simvastatin); and high-dose simvastatin (HSIM; CsA + 10 mg/kg simvastatin). Donor hearts from Fisher 344 rats were transplanted heterotopically into Lewis rat recipients. CsA was administered at 1.5 mg/kg/day for 2 weeks post-operatively. In addition, recipients were treated daily with simvastatin or vehicle for 8 weeks. Donor hearts were harvested for histopathologic and immunohistochemical examination. Intragraft concentration of chemokines and chemokine receptor expression were analyzed using enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction, respectively.


RESULTS
Both low and high doses of simvastatin significantly decreased the CAV score; inhibited recruitment of T lymphocytes and macrophages; reduced levels of intragraft MCP-1 (monocyte chemoattractant protein-1), RANTES (regulated on activation, normal T-cell expressed and secreted) protein and IP-10 (interferon-inducible protein-10); and down-regulated expression of chemokine receptors CCR2 and CCR5. CXCR3 expression was not affected by simvastatin treatment.


CONCLUSIONS
Our results demonstrate that simvastatin may attenuate CAV development, possibly through retarding intragraft chemokine accumulation and chemokine receptor expression.
Yin
Rong
R
Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, Nanjing, China.
Zhu
Jiaquan
J
Shao
Hongtao
H
Cheng
Xiaofeng
X
Feng
Xiaomei
X
Li
Zhongdong
Z
Jing
Hua
H
D000818:Animals; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D016027:Heart Transplantation; D007150:Immunohistochemistry; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism; D019707:Receptors, Chemokine / Q000187:drug effects* / Q000378:metabolism*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000494:pharmacology*; D014184:Transplantation, Homologous
D018932:Chemokine CCL2; D018946:Chemokine CCL5; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D019821:Simvastatin