ABSTRACT
Individuals suffering from systemic lupus erythematosus (SLE) are predisposed to accelerate cardiovascular disease. Our laboratory has recently developed an animal model of SLE-accelerated atherosclerosis. We have shown that, following 8 weeks feeding high fat Western diet, radiation chimeras consisting of SLE-derived haematopoietic cells transferred to low-density lipoprotein (LDL)r(-/-) mice (LDLr.Sle) have increased atherosclerosis compared with C57Bl/6 bone marrow recipients (LDLr.B6). However, this feeding regimen resulted in significant mortality in SLE-susceptible mice compared with controls with surviving animals having extremely elevated serum cholesterol (>500 mg/dL) and increased serum markers of kidney pathology. To test the hypothesis that SLE-associated autoimmune dysregulation can exacerbate atherosclerosis under more mild serum cholesterol conditions (approximately 200 mg/dL), we examined SLE and lesion development in radiation chimeras fed either a normal chow or high fat Western diet for 8 weeks. High fat fed LDLr.Sle mice exhibited increased mortality and were significantly more hypertensive. LDLr.Sle mice had greater titres of antibodies against dsDNA, oxLDL and phospholipid compared with controls. Lupus-susceptibility increased the atherosclerotic lesions and the percentage of CD4(+) T cells in the lesions of proximal aortas, independent of diet. These data show that increased dyslipidemia resulting from high-fat feeding can exacerbate autoimmunity and associated vascular complications. Conversely, they also show that autoimmune dysregulation can accelerate atherosclerosis in LDLr-deficient animals independent of feeding high fat diet. Collectively this study provides additional evidence that the accelerated atherosclerosis observed in SLE is autoimmune associated.
Subject(s)
Atherosclerosis , Dietary Fats/pharmacology , Lupus Erythematosus, Systemic , Receptors, LDL/genetics , Animals , Antibodies, Antiphospholipid/metabolism , Atherosclerosis/complications , Atherosclerosis/genetics , Atherosclerosis/immunology , Autoimmunity/immunology , Cholesterol, LDL/metabolism , Cholesterol, VLDL/metabolism , DNA/immunology , Dyslipidemias/complications , Dyslipidemias/genetics , Dyslipidemias/immunology , Lipoproteins, LDL/metabolism , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Receptors, LDL/metabolismABSTRACT
A solution to the long-standing problem presented by the oxidative cyclization of a phenolic 3-arylpropionamide to a spirolactam has been developed in this laboratory via oxazoline chemistry. This research was motivated by our interest in some novel tricyclic azaspirane natural products formally derived from tyrosine, such as FR901483 and TAN1251C. In this paper, we disclose full details of the total synthesis of these substances.
Subject(s)
Immunosuppressive Agents/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Aza Compounds/chemical synthesis , Spiro Compounds/chemical synthesisABSTRACT
[structure: see text]. The total synthesis of FR901483, a structurally novel immunosuppressant, has been accomplished by the use of technology recently developed in this laboratory for the oxidative cyclization of phenolic oxazolines to spirolactams. Our approach may reflect the biosynthetic pathway leading to the natural product.
Subject(s)
Immunosuppressive Agents/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Cyclization , Fungi/chemistry , Oxidation-ReductionABSTRACT
The oxidative cyclization of a phenolic amide to a spirolactam has long been regarded as an "impossible" reaction, because exposure of the substrates to a variety of oxidants results in formation of spirolactones with consequent loss of the amine segment. We recently communicated that this heretofore unknown transformation may be achieved by oxidation of oxazoline analogues of phenolic and indolic amides. Herein, we provide full details of our work.
