Apolipoprotein A-II Influences Apolipoprotein E-Linked Cardiovascular Disease Risk in Women with High Levels of HDL Cholesterol and C-Reactive Protein

Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups. Methodology/Principal: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I: A-II levels interacted with high apoE levels in establishing subgroup risk. Conclusions/Significance: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP

Alteration of the Immune-response During Cancer Development and Prevention By Administration of a Mycobacterial Antigen

It has been shown previously that A60, an antigen complex of Mycobacterium bovis BCG, triggers humoral and cellular immune reactions in vivo and lymphocyte-dependent macrophage activation in vitro. In the present work, the ability of A60 to prevent murine tumour development, in conjunction of not with irradiated isologous cancer cells, was explored with Taper liver tumour (TLT), a mammary-derived neoplasm (EMT6), and Lewis lung carcinoma (3LL). Repeated injections of A60 prior to challenge reduced the incidence of EMT6 and 3LL solid tumours and increased life span. This effect was enhanced by simultaneous administration of gamma-irradiated cancer cells (80-100% suppression of EMT6 and 3LL tumour growth). In mice developing or rejecting tumours, the status of humoral and cellular immunity was evaluated by A60-based immunoassays. Tumor development was accompanied by a rapid decrease of both anti-A60 IgG titre in blood and A60-triggered delayed hypersensitivity reactions. Moreover, A60-induced T lymphocyte proliferation and macrophage-dependent autologous cancer cell cytolysis declined progressively during the course of tumour growth. In case of successful immunotherapy, a pattern similar to that of unchallenged controls was observed. Our results suggest that A60 promotes cancer rejection via tumour infiltration by lymphocytes and macrophages activated by A60-specific T lymphocytes. An increased processing of tumour-specific antigens and activation of tumour-infiltrating lymphocytes is induced by administration of irradiated cancer cells in conjunction with A60

Ezetimibe inhibits expression of acid sphingomyelinase in liver and intestine

Ezetimibe inhibits cholesterol absorption in the intestine. Sphingomyelin has strong interactions with cholesterol. We investigated the effects of ezetimibe on Sphingomyelinase (SMase) expression in intestine and liver. After feeding rats with ezetimibe (5 mg/kg per day) for 14 days, acid SMase activities in the liver and in the proximal part of small intestine were reduced by 34 and 25%, respectively. Alkaline SMase (alk-SMase) was increased in the proximal part of the small intestine. Administration of lower doses of ezetimibe reduced acid SMase only in the liver by 14% (P < 0.05). In cell culture studies, ezetimibe decreased acid SMase activity in Hep G2 and Caco-2 cells dose-dependently. The reductions were more rapid for Hep G2 cells than for Caco-2 cells. Western blot showed that acid SMase protein was decreased in both Hep G2 and Caco-2 cells by 100 muM ezetimibe. The SM content was increased in Hep G2 cells but not Caco-2 cells, and total cholesterol content was increased in both cell lines 24 h after stimulation with 100 muM ezetimibe. Mevastatin, the inhibitor of cholesterol synthesis, induced a mild increase in acid SMase activity in Hep G2 cells but not Caco-2 cells. Following the reduction of acid SMase, ezetimibe at high dose slightly increased alk-SMase activity. In conclusion, the study demonstrates an inhibitory effect of ezetimibe on acid SMase activity and expression in both liver and intestine