Serine protease inhibitor A3 in atherosclerosis and aneurysm disease.

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.

Dendritic cells pulsed with malondialdehyde modified low density lipoprotein aggravate atherosclerosis in Apoe(-/-) mice.

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.

Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis.

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.