Specific loss of toll-like receptor 2 on bone marrow derived cells decreases atherosclerosis in LDL receptor null mice.

Innate immunity and, notably, Toll-like receptors (TLR), have an important role in atherogenesis. We have tested the hypothesis that the selective loss of TLR-2 by cells of bone marrow (BM) origin will protect low-density receptor-deficient (Ldlr (-/-)) mice from both early- and late-stage atherosclerosis. BM cells from Tlr2(+/+) and Tlr2(-/-) littermates were used to reconstitute lethally irradiated Ldlr(-/-) mice. Following a recovery period, mice were placed either on a diet containing 21% saturated fat - 0.15% cholesterol for 8 weeks to study early-stage atherosclerosis, or on a diet richer in cholesterol (1.5%) for 16 weeks to study late-stage atherosclerosis. Donor cell Tlr2 genotype did not alter serum cholesterol levels or lipoprotein profiles in recipient animals. After 8 weeks on the 0.15% cholesterol diet, deficiency of TLR-2 expression on cells of BM origin reduced atherosclerosis in the aortic root and the aortic arch in both genders of mice. In contrast, the BM recipients who received the 1.5% cholesterol diet for 16 weeks showed much larger lesions in the aortic root, and TLR-2 deficiency in BM cells failed to provide protection. Thus, TLR-2 expression in BM-derived cells contributes primarily to early stage atherosclerosis.

Effect of high-dose total body irradiation on ACTH, corticosterone, and catecholamines in the rat.

Total body irradiation (TBI) or partial body irradiation is a distinct risk of accidental, wartime, or terrorist events. Total body irradiation is also used as conditioning therapy before hematopoietic stem cell transplantation. This therapy can result in injury to multiple tissues and might result in death as a result of multiorgan failure. The hypothalamic-pituitary-adrenal (HPA) axis could play a causative role in those injuries, in addition to being activated under conditions of stress. In a rat model of TBI, we have established that radiation nephropathy is a significant lethal complication, which is caused by hypertension and uremia. The current study assessed HPA axis function in rats undergoing TBI. Using a head-shielded model of TBI, we found an enhanced response to corticotropin-releasing hormone (CRH) in vitro in pituitaries from irradiated compared with nonirradiated rats at both 8 and 70 days after 10-Gy single fraction TBI. At 70, but not 8 days, plasma adrenocorticotrophic hormone (ACTH) and corticosterone levels were increased significantly in irradiated compared with nonirradiated rats. Plasma aldosterone was not affected by TBI at either time point, whereas plasma renin activity was decreased in irradiated rats at 8 days. Basal and stimulated adrenal steroid synthesis in vitro was not affected by TBI. In addition, plasma epinephrine was decreased at 70 days after TBI. The hypothalamic expression of CRH messenger RNA (mRNA) and hippocampal expression of glucocorticoid receptor mRNA were unchanged by irradiation. We conclude that the hypertension of radiation nephropathy is not aldosterone or catecholamine-dependent but that there is an abscopal activation of the HPA axis after 10 Gy TBI. This activation was attributable at least partially to enhanced pituitary ACTH production.

Ionizing radiation alters hepatic cholesterol metabolism and plasma lipoproteins in Syrian hamster.

PURPOSE: The investigation of the effects of ionizing radiation on hepatic cholesterol metabolism and the concentration and composition of plasma lipoproteins in the male Syrian hamster. MATERIALS AND METHODS: After sublethal whole-body 60Co gamma-irradiation (8 Gy, 1 Gy/min), plasma lipoproteins were separated by density-gradient ultracentrifugation. Activities of hydroxymethylglutarylCoA (HMGCoA) reductase and of cholesterol 7alpha-hydroxylase were measured in hepatic microsomes and the low-density lipoprotein (LDL) receptor mass was determined in hepatic total membranes. Lipid peroxidation in LDL was assessed in vitro as the formation of conjugated dienes at 234 nm. A group of pair-fed animals served as controls as the food intake was markedly decreased with exposure to radiation. RESULTS: Plasma lipid concentrations decreased 2 days post-irradiation and then markedly increased by day 6 post-irradiation; plasma cholesterol was increased by 77% and triglycerides by +207%. LDL accumulated in plasma while high-density lipoprotein (HDL) levels decreased. HDL contained significant amounts of apo SAA, the acute phase apolipoprotein. The activities of hepatic HMGCoA reductase, the rate-limiting enzyme for cholesterol synthesis, increased (+125%, p=0.06); hepatic cholesterol 7alpha-hydroxylase, the rate-limiting enzyme for bile acid synthesis, decreased (-85%); and the hepatic LDL receptor mass also decreased (-44%). The susceptibility of LDL to oxidation was also increased when animals were exposed to radiation. CONCLUSIONS: Lipoprotein modifications that appeared following radiation exposure may result from an induced inflammatory state and may further contribute to vascular damage.

Exposure to long wavelength ultraviolet radiation decreases processing of low density lipoprotein by cultured human fibroblasts.

Exposure of MRC5 human fibroblasts to UVA radiation (365 nm) resulted in a dose-dependent decrease in low density lipoprotein (LDL) uptake and degradation by cells. Following a 25 J/cm2 irradiation dose, about 45% and 70% reduction in 125I-LDL uptake and degradation were observed, respectively. Under the same conditions, the 14C-sucrose uptake was also decreased to about the same extent as LDL uptake. Cell pretreatment with the antioxidants vitamin E and vitamin C did not prevent the UVA-induced fall in LDL degradation. These results point to the possible effects of UVA radiation on receptor-mediated and nonspecific uptake of exogenous molecules. With special regard to the alterations in receptor-mediated processing of exogenous ligands, such a phenomenon could be of importance in UVA-induced skin degenerative processes.