muramidase and Hyperlipidemias

Although the molecular components of circadian rhythms oscillate in discrete cellular components of the vasculature and many aspects of vascular function display diurnal variation, the cellular connections between the molecular clock and inflammatory cardiovascular diseases remain to be elucidated. Previously we have shown that pre- versus postnatal deletion of Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1), the nonredundant core clock gene has contrasting effects on atherogenesis. Here we investigated the effect of myeloid cell Bmal1 deletion on atherogenesis and abdominal aortic aneurysm formation in mice. Approach and Results: Mice lacking Bmal1 in myeloid cells were generated by crossing Bmal1 flox/flox mice with lysozyme 2 promoter-driven Cre recombinase mice on a hyperlipidemic low-density lipoprotein receptor-deficient background and were fed on a high-fat diet to induce atherosclerosis. Atherogenesis was restrained, concomitant with a reduction of aortic proinflammatory gene expression in myeloid cell Bmal1 knockout mice. Body weight, blood pressure, blood glucose, triglycerides, and cholesterol were unaltered. Similarly, myeloid cell depletion of Bmal1 also restrained Ang II (angiotensin II) induced formation of abdominal aortic aneurysm in hyperlipidemic mice. In vitro, RNA-Seq analysis demonstrated a proinflammatory response in cultured macrophages in which there was overexpression of Bmal1.. Myeloid cell Bmal1 deletion retards atherogenesis and restrains the formation of abdominal aortic aneurysm and may represent a potential therapeutic target for inflammatory cardiovascular diseases.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Abdominal; ARNTL Transcription Factors; Atherosclerosis; Cells, Cultured; Crosses, Genetic; Diet, High-Fat; Gene Deletion; Gene Expression; Hyperlipidemias; Inflammation; Integrases; Macrophages, Peritoneal; Mice; Mice, Knockout; Muramidase; Myeloid Cells; Promoter Regions, Genetic; Receptors, LDL

Hyperlipidemia promotes oxidant stress, inflammation, and atherogenesis in apolipoprotein E-deficient (ApoE((-/-))) mice. Mice transgenic for lysozyme (LZ-Tg) are resistant to acute and chronic oxidative stress and have decreased circulating levels of pro-oxidant advanced glycation end-products (AGEs). Herein we report that TIB-186 macrophages transduced with adenovirus-expressing human LZ (AdV-LZ) containing the AGE-binding domain facilitated AGE uptake and degradation and that AdV-LZ-transduced macrophages and peritoneal macrophages from LZ-Tg mice suppressed the AGE-triggered tumor necrosis factor-alpha response. We assessed atherosclerosis in LZ-Tg mice crossed with ApoE((-/-)) mice (LZ/ApoE((-/-))) and found increased serum LZ levels and decreased AGE and 8-isoprostanes levels, although hyperlipidemia remained similar to ApoE((-/-)) controls. Atherosclerotic plaques and neointimal lesions at the aortic root and descending aorta were markedly decreased (by 40% and 80%, respectively) in LZ/ApoE((-/-)) versus ApoE((-/-)) mice, as were inflammatory infiltrates. The arterial lesions following femoral artery injury in LZ/ApoE((-/-)) mice were suppressed (intimal to media ratio decreased by 50%), as were AGE deposits and vascular smooth muscle cell activation, compared to ApoE((-/-)) mice. Despite hyperlipidemia, development of atheroma and occlusive, inflammatory arterial neointimal lesions in response to injury was suppressed in LZ/ApoE((-/-)) mice. This effect may be due to the antioxidant properties of LZ, which is possibly linked to the AGE-binding domain region of the molecule.

Topics: Adenoviridae; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blotting, Western; Cells, Cultured; Femoral Artery; Genetic Vectors; Glycation End Products, Advanced; Humans; Hyperlipidemias; Immunohistochemistry; Macrophages; Mice; Mice, Transgenic; Muramidase; Muscle, Smooth, Vascular; Recombinant Proteins; RNA, Messenger; Transduction, Genetic; Tumor Necrosis Factor-alpha

The lysocyme activity in blood serum and liver hemogenate of rats and rabbits at hyperlipidemia and atherosclerosis and its treatment with some new compounds or chemicals has been studied. A change of natural resistance of the body at hyperlipidemia and atherosclerosis characterized by the increase of serum lysocyme activity has been found. Preparations used in this work exerted mobilizing effect on the level of serum lysocyme activity but their influence on the functional state of the liver was different.

Topics: Adjuvants, Immunologic; Animals; Arteriosclerosis; Enzyme Activation; Hypercholesterolemia; Hyperlipidemias; Hypolipidemic Agents; Immunity, Innate; Liver; Muramidase; Niacin; Rabbits; Rats; Triglycerides

Topics: Colitis, Ulcerative; Enzyme Activation; Humans; Hyperlipidemias; Hypoproteinemia; Muramidase; Serum Albumin; Serum Globulins

Hepatic vein thrombosis initiated by an intravenous injection of endotoxin (Salmonella typhosa, 0.3 mg/kg) resulted in an incidence of 78% in rats fed a butter-rich diet (group 1). On the other hand, no lesion could be produced in control animals fed corn oil (group 2) or standard chow (group 3). In regard to the respective thrombotic tendencies, the rats fed butter showed higher circulating levels of factor XII (175% vs 140% in group 2 and 100% in group 3) and a far more severe decrease in this factor (41% vs 15% in group 2 and 7% in group 3) and in platelets (48% vs 25% in group 2 and 19% in group 3) 2 hours after the injection of endotoxin. The triggering effect of endotoxin could be reproduced by ellagic acid, a known activator of factor XII. Given by slow infusion (1 mg/kg/min) this chemical induced hepatic vein thrombosis in 52% of the rats fed the butter-rich diet. Furthermore, inhibition of factor XII activation by lysozyme (20 mg/kg/min) completely prevented hepatic vein thrombosis initiated by endotoxin in butter-fed animals. It is concluded that, in addition to the potent hypercoagulability induced by the fat-rich diets, activation of Hageman factor consecutive to endotoxin injection is essential for production of the phenomenon of hepatic vein thrombosis.

Topics: Animals; Benzopyrans; Blood Cell Count; Blood Platelets; Butter; Diet, Atherogenic; Dietary Fats; Endotoxins; Factor XII; Hematocrit; Hemostatics; Hepatic Veins; Hyperlipidemias; Injections, Intravenous; Male; Muramidase; Oils; Rats; Salmonella typhi; Thrombophlebitis; Zea mays

Topics: Adaptation, Physiological; Adrenocortical Hyperfunction; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bacterial Vaccines; Blood Coagulation Disorders; Blood Glucose; Blood Protein Disorders; Child; Cholesterol; Complement System Proteins; Electrolytes; Eosinophils; Humans; Hyperlipidemias; Leukocytosis; Lymphopenia; Muramidase; Neurologic Manifestations; Phagocytosis; Properdin; Thrombocytosis; Toxoids; Transferrin; Vaccination; Viral Vaccines