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Remodeling of extracellular matrix (ECM) plays an important role in both atherosclerosis and aneurysm disease. Serine protease inhibitor A3 (serpinA3) is an inhibitor of several proteases such as elastase, cathepsin G and chymase derived from mast cells and neutrophils. In this study, we investigated the putative role of serpinA3 in atherosclerosis and aneurysm formation. SerpinA3 was expressed in endothelial cells and medial smooth muscle cells in human atherosclerotic lesions and a 14-fold increased expression of serpinA3n mRNA was found in lesions from Apoe-/- mice compared to lesion-free vessels. In contrast, decreased mRNA expression (-80%) of serpinA3 was found in biopsies of human abdominal aortic aneurysm (AAA) compared to non-dilated aortas. Overexpression of serpinA3n in transgenic mice did not influence the development of atherosclerosis or CaCl2-induced aneurysm formation. In situ zymography analysis showed that the transgenic mice had lower cathepsin G and elastase activity, and more elastin in the aortas compared to wild-type mice, which could indicate a more stable aortic phenotype. Differential vascular expression of serpinA3 is clearly associated with human atherosclerosis and AAA but serpinA3 had no major effect on experimentally induced atherosclerosis or AAA development in mouse. However, serpinA3 may be involved in a phenotypic stabilization of the aorta.

Background: Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic vascular inflammation with an autoimmune response to low-density lipoprotein components., Methods and Results: To dampen the inflammatory component of atherosclerosis, we injected hypercholesterolemic huB100(tg) × Ldlr(-/-) mice (mice transgenic for human apolipoprotein B100 [ApoB100] and deficient for the low-density lipoprotein receptor) intravenously with dendritic cells (DCs) that had been pulsed with the low-density lipoprotein protein ApoB100 in combination with the immunosuppressive cytokine interleukin-10. DCs treated with ApoB100 and interleukin-10 reduced proliferation of effector T cells, inhibited production of interferon-γ, and increased de novo generation of regulatory T cells in vitro. Spleen cells from mice treated with DCs plus ApoB100 plus interleukin-10 showed diminished proliferative responses to ApoB100 and significantly dampened T-helper 1 and 2 immunity to ApoB100. Spleen CD4(+) T cells from these mice suppressed activation of ApoB100-reactive T cells in a manner characteristic of regulatory T cells, and mRNA analysis of lymphoid organs showed induction of transcripts characteristic of these cells. Treatment of huB100(tg) × Ldlr(-/-) mice with ApoB100-pulsed tolerogenic DCs led to a significant (70%) reduction of atherosclerotic lesions in the aorta, with decreased CD4(+) T-cell infiltration and signs of reduced systemic inflammation., Conclusions: Tolerogenic DCs pulsed with ApoB100 reduced the autoimmune response against low-density lipoprotein and may represent a novel possibility for treatment or prevention of atherosclerosis.

Objective: Atherosclerosis is an inflammatory disease involving activation of adaptive and innate immune responses to modified lipoproteins. Dendritic cells (DCs), which are professional antigen-presenting cells that activate T cells, are present in atherosclerotic lesions but their role for atherosclerosis-related immunity is unclear., Methods and Results: To evaluate the role of DC in atherosclerosis, DCs pulsed with malondialdehyde modified low density lipoprotein (MDA-LDL) were transferred into Apoe(-/-) mice. The extent of disease was measured in the aortic root and was compared to that in animals treated with Keyhole Limpet Hemocyanin (KLH) pulsed DCs and to untreated animals. Mice receiving MDA-LDL pulsed DCs showed significantly larger atherosclerotic lesions compared to controls, with increased inflammation in the lesions and antigen-specific immune responses. Furthermore, MDA-LDL administration in complete Freund's adjuvant, which is atheroprotective, led to the induction of regulatory T cells whereas MDA-LDL-DCs treatment did not, suggesting that modulation of immune properties can result in different effects on atherosclerosis., Conclusions: DCs presenting components of LDL promote specific immunity to their antigen, increase lesion inflammation and accelerate atherosclerosis., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: The pathogenesis of atherosclerosis involves inflammation and immune reactions. Low-density lipoproteins accumulate and are oxidized (oxLDL) in the arterial intima during hypercholesterolemia, leading to activation of endothelial cells, macrophages and T cells. We have previously found that severe hypercholesterolemia can induce a switch of autoimmune responses from T helper (Th)1 to Th2 effector type in atherosclerotic apoE knockout (E0) mice. The present study was performed to investigate whether Th3 immune effector responses and their inducing cytokine, transforming growth factor-beta (TGF-beta) are affected by hypercholesterolemia., Methods and Results: In E0 mice fed with high cholesterol diet and in C57BL/6J mice treated with poloxamer P-407, an agent that elevates plasma cholesterol and triglycerides, severe hypercholesterolemia led to elevated circulating TGF-beta1 levels, increased TGF-beta1(+)CD4(+) Th3 cells in lesions and spleen, and increased Th3 dependent IgG2b antibodies to oxLDL. A positive correlation was observed between plasma TGF-beta1 and cholesterol levels and between plasma TGF-beta1 and IgG2b anti-oxLDL., Conclusions: Such elevation of TGF-beta may increase the stability of plaques by inhibiting T cell responses and macrophage activation and by stimulating collagen synthesis. This new finding could be important in the regulation of immune activity, inflammation and fibrosis in the atherosclerotic plaque.

Objective: Atherosclerosis is associated with immune responses to oxidized low-density lipoprotein (oxLDL). The presence of activated macrophages and T cells in lesions suggests that cell-mediated immune reactions are taking place during the disease process. However, the role of specific immune responses has remained unclear. We have previously shown that transfer of CD4+ T cells from apolipoprotein E knockout mice (apoE(-/-)) into immunodeficient apoE(-/-) scid/scid mice accelerates disease., Methods and Results: To test whether this effect is dependent on specific disease-associated antigens, purified CD4+ T cells from oxLDL-immunized mice were transferred into apoE(-/-) scid/scid mice. CD4+ T cells from mice immunized with a nonrelevant antigen, keyhole limpet hemocyanin (KLH), and naïve CD4+ T cells were used as controls. After 12 weeks, all mice that received T cells had larger lesions than untouched apoE(-/-) scid/scid controls. However, mice receiving CD4+ T cells from oxLDL immunized mice had substantially accelerated lesion progression compared with those receiving naive or KLH-primed T cells. Circulating levels of interferon-gamma were increased in proportion to the acceleration of atherosclerosis., Conclusions: These data show that adoptive transfer of purified CD4+ T cells from oxLDL-immunized mice accelerates atherosclerosis. They support the notion that Th1 cellular immunity is proatherogenic and identify oxLDL as a culprit autoantigen.

Atherosclerosis is an inflammatory disease. T lymphocytes, occurring concomitantly with macrophages, are found in atherosclerotic lesions with substantial numbers in all stages. Most of the T cells in the lesions are CD4+ T cells. The finding of activated T cells and macrophages in lesions and cloning of T cells specific for modified low-density lipoproteins from lesions suggest that a cell-mediated immune reaction is taking place in atherosclerosis. This review provides an overview of our current understanding of the roles of CD4+ T cell subpopulations in atherosclerosis. [Copyright &y& Elsevier]

Atherosclerosis is an inflammatory disease elicited by a lipid metabolic disturbance at sites of hemodynamic strain. Careful clinical and histopathological studies in humans as well as investigations in experimental models have identified all these phenomena, i.e. inflammation, metabolism, and hemodynamics, as playing key roles in the initiation and progression of atherosclerotic cardiovascular disease. While in-depth research into the regulation of cholesterol metabolism and blood pressure has led to new therapies against atherosclerotic cardiovascular diseases, our understanding of the inflammatory component of atherosclerosis remains incomplete and will require further research before new therapeutic or preventive strategies can be developed. This brief review will discuss new data regarding the regulation of proatherosclerotic, adaptive immunity, which is a strong driving force for the inflammatory process in the atherosclerotic plaque. [Copyright &y& Elsevier]

Abstract: Objective: Atherosclerosis is an inflammatory disease involving activation of adaptive and innate immune responses to modified lipoproteins. Dendritic cells (DCs), which are professional antigen-presenting cells that activate T cells, are present in atherosclerotic lesions but their role for atherosclerosis-related immunity is unclear. Methods and results: To evaluate the role of DC in atherosclerosis, DCs pulsed with malondialdehyde modified low density lipoprotein (MDA-LDL) were transferred into Apoe −/− mice. The extent of disease was measured in the aortic root and was compared to that in animals treated with Keyhole Limpet Hemocyanin (KLH) pulsed DCs and to untreated animals. Mice receiving MDA-LDL pulsed DCs showed significantly larger atherosclerotic lesions compared to controls, with increased inflammation in the lesions and antigen-specific immune responses. Furthermore, MDA-LDL administration in complete Freund''s adjuvant, which is atheroprotective, led to the induction of regulatory T cells whereas MDA-LDL-DCs treatment did not, suggesting that modulation of immune properties can result in different effects on atherosclerosis. Conclusions: DCs presenting components of LDL promote specific immunity to their antigen, increase lesion inflammation and accelerate atherosclerosis. [Copyright &y& Elsevier]