Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.

Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.

Background-Monocytes are critical mediators of atherogenesis. Deletion of individual chemokines or chemokine receptors leads to significant but only partial inhibition of lesion development, whereas deficiency in other signals such as CXCL16 or CCR1 accelerates atherosclerosis. Evidence that particular chemokine pathways may cooperate to promote monocyte accumulation into inflamed tissues, particularly atherosclerotic arteries, is still lacking. Methods and Results-Here, we show that chemokine-mediated signals critically determine the frequency of monocytes in the blood and bone marrow under both noninflammatory and atherosclerotic conditions. Particularly, CCL2-, CX3CR1-, and CCR5-dependent signals differentially alter CD11b ϩ Ly6G Ϫ 7/4 hi (also known as Ly6C hi ) and CD11b ϩ Ly6G Ϫ 7/4 lo (Ly6C lo ) monocytosis. Combined inhibition of CCL2, CX3CR1, and CCR5 in hypercholesterolemic, atherosclerosis-susceptible apolipoprotein E-deficient mice leads to abrogation of bone marrow monocytosis and to additive reduction in circulating monocytes despite persistent hypercholesterolemia. These effects are associated with a marked and additive 90% reduction in atherosclerosis. Interestingly, lesion size highly correlates with the number of circulating monocytes, particularly the CD11b ϩ Ly6G Ϫ 7/4 lo subset. Conclusions-CCL2, CX3CR1, and CCR5 play independent and additive roles in atherogenesis. Signals mediated through these pathways critically determine the frequency of circulating monocyte subsets and thereby account for almost all macrophage accumulation into atherosclerotic arteries. (Circulation. 2008;117:1649-1657.)

Abstract-Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of evidence supports a role for proinflammatory mediators in disease progression, the understanding of the role of the antiinflammatory component in the modulation of plaque progression is only at its beginning. TGF-␤1, -␤2, and -␤3 are cytokines/growth factors with broad activities on cells and tissues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the direct role of TGF-␤ in the development and composition of advanced atherosclerotic lesions. In the present study, we show that inhibition of TGF-␤ signaling using a neutralizing anti-TGF-␤1, -␤2, and -␤3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mice. Moreover, inhibition of TGF-␤ signaling favors the development of lesions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-␤ in atherosclerosis.

Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3- and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.

Background— Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood. Methods and Results— Here, we show that milk fat globule-EGF factor 8 (Mfge8, also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow–derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon-γ production in both the spleen and the atherosclerotic arteries. In addition, we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis. Conclusions— Lack of Mfge8 in bone marrow–derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response, which leads to an acceleration of plaque development.

Objective-To study the role of Mer receptor tyrosine kinase (mertk) in atherosclerosis. Methods and Results-We irradiated and reconstituted atherosclerosis-susceptible C57Bl/6 low-density lipoprotein receptor-deficient female mice (ldlr Ϫ/Ϫ ) with either a mertk ϩ/ϩ or mertk Ϫ/Ϫ (tyrosine kinase-defective mertk) bone marrow. The mice were put on high-fat diet for either 8 or 15 weeks. Mertk deficiency led to increased accumulation of apoptotic cells within the lesions, promoted a proinflammatory immune response, and accelerated lesion development.

Abstract-Members of the Rho family of small GTPases have been recently implicated in inflammatory signaling. We examined the effect of in vivo inhibition of Rho kinase on atherogenesis in mice. Low-density lipoprotein receptor (LDLR) knockout (KO) mice fed a cholate-free high-fat diet received daily intraperitoneal injection of saline (nϭ8, control group) or Y-27632 (30 mg/kg, nϭ9), a specific Rho kinase inhibitor. After 9 weeks, Y-27632 treatment resulted in significant in vivo inhibition of Rho kinase activity (Pϭ0.004). Body weights, arterial blood pressures, and plasma cholesterol levels were comparable in both groups. Atherosclerotic lesion size in the aortic sinus and thoracic aorta of mice treated with Y-27632 was reduced by respectively 35% and 29% in comparison with the saline-treated animals (Pϭ0. 006 and Pϭ0.03, respectively). This was associated with a significant reduction in T lymphocyte accumulation (Pϭ0.035) and expression of p65 subunit of NF-B within plaques (PϽ0.05). In vitro, treatment with Y-27632 inhibited p65 phosphorylation and degradation of IB␣ in mouse peritoneal macrophages and significantly inhibited concanavalin A-induced proliferation of spleen-derived T cells (PϽ0.001). Key Words: atherosclerosis Ⅲ inflammation Ⅲ lymphocytes Ⅲ signal transduction Ⅲ nuclear factor-B A therosclerosis is the leading cause of cardiovascular morbidity and mortality in the world. Recent consistent studies from several groups have elucidated the critical role of inflammation in the development and complications of atherosclerosis. [1][2][3][4] However, despite the increasing knowledge regarding the role of inflammation in atherogenesis, the precise intracellular transduction pathways involved in this process remain unknown. Recent studies reported enhanced activation of the transcription factor nuclear factor-B (NF-B) after a high-fat cholate-free diet in LDLR KO mice, 5 but its direct role or that of other signaling pathways in atherogenesis was not assessed.Small G proteins of the Rho family, initially described as key regulators of the actin cytoskeleton, are now known to play a major role in many biological processes including calcium sensitization of smooth muscle contraction, migration, gene transcription, proliferation, and transformation. 6,7 They have also been implicated in the regulation of signal transduction cascades related to inflammation, particularly the JNK and NF-B pathways. 6 -9 These cellular functions and transduction pathways may be relevant to the atherogenic process. However, although a role for Rho/Rho kinase activation has been recently reported in experimental models of vascular inflammation or injury, 10 -13 hitherto no information is available regarding the role of Rho kinase in atherosclerosis. Therefore, we examined the effects of in vivo inhibition of the Rho effector, Rho kinase, on the development of early atherosclerosis in LDLR KO mice. Materials and Methods MiceSeventeen 10-week-old C57BL/6J LDLR KO mice (kindly provided by Dr Francis Bayard, Toulouse, France) were p...