The molecular mechanisms predisposing to atherosclerotic aneurysm formation remain undefined. Nevertheless, rupture of aortic aneurysms is a major cause of death in Western societies, with few available treatments and poor long-term prognosis. Indirect evidence suggests that matrix metalloproteinases (MMPs) and plasminogen activators (PAs) are involved in its pathogenesis. MMPs are secreted as inactive zymogens (pro-MMPs), requiring activation in the extracellular compartment. Plasmin, generated from the zymogen plasminogen by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA; refs 14,15), has been proposed as a possible activator in vitro, but evidence for such a role in vivo is lacking. Analysis of atherosclerotic aorta in mice with a deficiency of apoliprotein E (Apoe-/-; ref. 18), singly or combined with a deficiency of t-PA (Apoe-/-:Plat-/-) or of u-PA (Apoe-/-:Plau-/-; ref. 19), indicated that deficiency of u-PA protected against media destruction and aneurysm formation, probably by means of reduced plasmin-dependent activation of pro-MMPs. This genetic evidence suggests that plasmin is a pathophysiologically significant activator of pro-MMPs in vivo and may have implications for the design of therapeutic strategies to prevent aortic-wall destruction by controlling Plau gene function.

Rationale: Aggravated atherosclerosis in B lymphocyte-deficient chimeric mice and reduced atherosclerosis after transfer of unfractionated spleen B lymphocytes into splenectomized mice have led to the widely held notion that B lymphocytes are atheroprotective. However, B lymphocytes can be pathogenic, because their depletion by anti-CD20 antibody ameliorated atherosclerosis, and transfer of B2 lymphocytes aggravated atherosclerosis. These observations raise the question of the identity of the atheroprotective B-lymphocyte population.Objective: The purpose of the study was to identify an atheroprotective B-lymphocyte subset and mechanisms by which they confer atheroprotection. Methods and Results:

Accumulation of T cells and macrophages in athero-sclerotic plaques and the formation of antibodies directed against plaque proteins suggests that adaptive immunity contributes to the development of atherosclerosis. The contribution of Th1 and Th2 helper cell subsets to atherogenesis was studied in a murine model by interbreeding apolipoprotein E-deficient (apoE mice with mice deficient in key cytokines that drive either Th1 responses [interleukin (IL)-12] or Th2 responses (IL-4). Compared to apoE؊/؊ mice, apoE ؊/؊ /IL-12 ؊/؊ mice had a 52% reduction in plaque area in the aortic root at 30 weeks of age (P < 0.001). ApoE ؊/؊ /IL-4 ؊/؊ mice had a 27% reduction in plaque area compared to apoE ؊/؊ mice (P < 0.05) at 30 weeks of age, but their plaques were significantly larger than in apoE ؊/؊ /IL-12 ؊/؊ mice at this stage (P < 0.05). By 45 weeks of age, there were no significant differences in lesion sizes in the aortic root between the strains, however apoE ؊/؊ /IL-4 ؊/؊ mice showed a 58% and 64% decrease in disease in their aortic arch compared to apoE ؊/؊ (P < 0.05) and apoE ؊/؊ /IL-12 ؊/؊ (P < 0.05) mice, respectively, and a 78% decrease in thoracic lesions compared to apoE ؊/؊