Abstract 1738: Inhibition of the Interaction between Platelet Factor 4 and RANTES Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice
Atherosclerotic cardiovascular disease is becoming a major threat in the Western society and is now regarded as an inflammatory disease in which monocytic cell recruitment to atherosclerotic lesions is a key mechanism. Platelets facilitate the arrest of monocytes by depositing chemokines such as the monocyte attractant RANTES and Platelet Factor 4 (PF4) on activated endothelium. Recently we found that PF4 engages heterophilic interactions with RANTES, thereby potentiating RANTES-induced monocyte arrest, suggesting that PF4 positively influences the pro-atherogenic effects of RANTES. We hypothesized that disruption of the interaction of PF4 with RANTES may attenuate the pro-inflammatory effects of RANTES. Evaluation of the RANTES and PF4 tertiary structures allowed us to design a peptide antagonist, designated CKEY2. CKEY2 was found to dose-dependently inhibit the interaction of RANTES and PF4 as assessed by surface plasmon resonance and isothermal fluorescence titration spectroscopy. In addition, CKEY2 was found to inhibit the stimulatory effect of PF4 on RANTES-induced monocyte arrest on activated HUVEC in vitro. Interestingly, the chemotactic and arrest-promoting effects of RANTES alone were not affected by CKEY2, although CKEY2 was found to interact strongly with RANTES. The murine counterpart of CKEY2, termed MKEY, also inhibited the interaction between murine PF4 and RANTES. When Apolipoprotein E(ApoE)-deficient mice received intraperitoneal injections of MKEY during the period in which they were fed an atherogenic diet, they showed a marked reduction in atherosclerotic plaque formation in the abdominal aorta, compared with mice receiving control peptide. In addition, intimal hyperplasia in the brachiocephalic artery was also reduced in the mice that received MKEY. These data indicate that the enhancement of RANTES-induced monocyte arrest by PF4 is a relevant process in the formation of atherosclerotic lesions. Moreover, inhibition of the interaction of PF4 and RANTES attenuates atherosclerosis in ApoE-deficient mice and may pose an attractive target in the prevention of atherosclerosis and neointima formation after intervention.