Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells.

BACKGROUND: Studies to define the overall contribution of lymphocytes to lesion formation in atherosclerosis-susceptible mice have demonstrated relatively subtle effects; the use of lymphocyte-deficient mice, however, compromises both the effector and regulatory arms of the immune system. Here, we tested the hypothesis that deletion of CXCL10 (IP-10), a chemokine specific for effector T cells that has been localized within atherosclerotic lesions, would significantly inhibit atherogenesis. METHODS AND RESULTS: Compound deficient Apoe(-/-)/Cxcl10(-/-) mice fed a Western-style diet for either 6 or 12 weeks demonstrated significant reductions in atherogenesis as compared with Apoe(-/-) controls, as assessed by both aortic en face and cross-sectional analyses. Immunohistochemical studies revealed a decrease in the accumulation of CD4+ T cells, whereas quantitative polymerase chain reaction analysis of lesion-rich aortic arches demonstrated a marked reduction in mRNA for CXCR3, the CXCL10 chemokine receptor. Although overall T-cell accumulation was diminished significantly, we found evidence to suggest that regulatory T-cell (Treg) numbers and activity were enhanced, as assessed by increased message for the Treg-specific marker Foxp3, as well as increases in immunostaining for the Treg-associated cytokines interleukin-10 and transforming growth factor-beta1. We also documented naturally occurring Treg cells in human atherosclerotic lesions. CONCLUSIONS: We provide novel evidence for a functional role for the effector T-cell chemoattractant CXCL10 in atherosclerotic lesion formation by modulating the local balance of the effector and regulatory arms of the immune system.

Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment.

BACKGROUND: It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB4), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB(4) signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown. METHODS AND RESULTS: To directly assess the role of the LTB4-BLT1 pathway in atherogenesis, we bred BLT1(-/-) mice into the atherosclerosis-susceptible apoE(-/-) strain. Compound-deficient apoE(-/-)/Blt1(-/-) mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE(-/-) controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1(+/+) SMCs and absent in Blt1(-/-) cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions. CONCLUSIONS: These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.

Two-year safety and effectiveness of sirolimus-eluting stents (from a prospective registry).

Uncertainty exists about the long-term safety and efficacy outcomes of sirolimus-eluting stents (SESs) in unselected patients. The present study was performed to evaluate the safety and efficacy of the SES in treatment of patients with coronary artery disease in an unselected population. Over a 2-year period, 1,504 consecutive patients undergoing percutaneous coronary intervention with ≥1 SES were enrolled. The primary end point was the occurrence of target vessel failure (TVF; a composite of cardiac death, myocardial infarction, or clinically driven target vessel revascularization). An independent clinical event committee adjudicated all adverse events up to 2-year follow-up. Dual antiplatelet therapy was recommended for ≥1 year throughout the study period. Mean age was 65 ± 11 years; 75% were men, and 34% were diabetics. SESs were implanted for off-label indications in 86% of cases. TVF rates were 3.3%, 6.9%, 11.5%, and 15.5% at 30-day, 6-month, 1-year, and 2-year follow-ups, respectively. The 2-year cumulative rate of definite/probable stent thrombosis was 0.9%; 0.2% was very late thrombosis, occurring from 1 year to 2 years. Patients off dual antiplatelet therapy at 6 months had a significantly increased rate of subsequent death from noncardiac causes. Patients off dual antiplatelet therapy at 1 year had a significantly decreased rate of subsequent clinically driven target lesion revascularization. In conclusion, use of SESs in unselected patients with coronary artery disease was associated with a low TVF rate at 2 years with an acceptable incidence of stent thrombosis.