ABSTRACT
In view of its multifaceted anti-inflammatory properties, interleukin-10 (IL-10) has been deemed to be potentially anti-atherogenic. We have evaluated the capacity of adenoviral gene transfer of IL-10 for the modulation of de novo atherosclerotic lesion formation by systemic and by local overexpression. Atherogenesis was initiated in the carotid arteries of low-density lipoprotein receptor deficient mice by perivascular placement of silastic collars. One week after collar placement, mice were injected intravenously with 1 x 109 plaque-forming units (pfu's) of IL-10 (AdV.IL-10) or control adenovirus (AdV.empty). Administration of AdV.IL-10 resulted in extended systemic expression of IL-10 (peak serum level 3.0 +/- 1.1 ng/ml) and a reduction in atherosclerotic lumen stenosis by 62.2% (P<0.02). This finding was accompanied by monocyte deactivation and lowering of serum cholesterol levels (maximum decrease 44%). In a second experiment, collared arteries were transfected locally by transluminal instillation of adenovirus (titer 1.5x1010 pfu/ml). Systemic parameters remained unchanged following local transfection, but the degree of stenosis was, nonetheless, decreased by 44.9% (P<0.05). We conclude that a marked inhibition of atherogenesis can be achieved by systemic overexpression of AdV.IL-10, owing to its metabolic and immunomodulatory effects. Local IL-10 transfer is virtually equipotent, however, and it may represent a valuable addition to the armory of anti-atherosclerotic therapies.
Subject(s)
Arteriosclerosis/therapy , Genetic Therapy , Interleukin-10/genetics , Receptors, LDL/genetics , Adenoviridae/genetics , Animals , Arteriosclerosis/genetics , Arteriosclerosis/pathology , Carotid Artery Diseases/genetics , Carotid Artery Diseases/pathology , Carotid Artery Diseases/therapy , Cholesterol/blood , Constriction , Female , Gene Expression Regulation , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Humans , Interleukin-10/blood , Interleukin-10/therapeutic use , Macrophages/pathology , Mice , Mice, Knockout , Monocytes/immunology , Monocytes/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Interleukin/genetics , Receptors, Interleukin-10 , Receptors, LDL/deficiency , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The suprachiasmatic nucleus (SCN), the biological clock, is responsible for a 24-h rhythm in plasma glucose concentrations, with the highest concentrations toward the beginning of the activity period. To investigate whether the SCN is also responsible for daily fluctuations in glucose uptake and to examine how these fluctuations relate to the rhythm in plasma glucose concentrations, SCN-intact rats and SCN-lesioned rats were injected intravenously with a glucose bolus at different time points. We found an increase in glucose uptake toward the beginning of the activity period, followed by a gradual reduction in glucose uptake toward the end of the activity period. The daily variation in glucose tolerance seemed not to be caused by fluctuations in insulin responses of the pancreas but by a daily variation in insulin sensitivity. Lesioning the SCN resulted in the disappearance of the daily fluctuation in glucose uptake and insulin sensitivity. Interestingly, SCN-lesioned rats showed an enhancement in glucose tolerance that could not be explained by higher insulin responses or enhanced insulin sensitivity. Therefore, these findings suggest a role for the SCN in insulin-independent glucose uptake. The present results further show that the daily rhythm in glucose tolerance follows the same pattern as the daily rhythm in plasma glucose concentrations. We hypothesized that the biological clock prepares the individual for the upcoming activity period by two separate mechanisms: increasing plasma glucose concentrations and making tissue more tolerant to glucose.
