Background-Strengthening the macrophage glutathione redox buffer reduces macrophage content and decreases the severity of atherosclerotic lesions in LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice, but the underlying mechanisms were not clear. This study examined the effect of metabolic stress on the thiol redox state, chemotactic activity in vivo, and the recruitment of macrophages into atherosclerotic lesions and kidneys of LDL-R Ϫ/Ϫ mice in response to mild, moderate, and severe metabolic stress. Methods and Results-Reduced glutathione (GSH) and glutathione disulfide (GSSG) levels in peritoneal macrophages isolated from mildly, moderately, and severe metabolically-stressed LDL-R Ϫ/Ϫ mice were measured by HPLC, and the glutathione reduction potential (E h ) was calculated. Macrophage E h correlated with the macrophage content in both atherosclerotic (r 2 ϭ0.346, Pϭ0.004) and renal lesions (r 2 ϭ0.480, Pϭ0.001) in these mice as well as the extent of both atherosclerosis (r 2 ϭ0.414, Pϭ0.001) and kidney injury (r 2 ϭ0.480, Pϭ0.001). Compared to LDL-R Ϫ/Ϫ mice exposed to mild metabolic stress, macrophage recruitment into MCP-1-loaded Matrigel plugs injected into LDL-R Ϫ/Ϫ mice increased 2.6-fold in moderately metabolically-stressed mice and 9.8-fold in severely metabolically-stressed mice. The macrophage E h was a strong predictor of macrophage chemotaxis (r 2 ϭ0.554, PϽ0.001). Conclusion-Thiol oxidative stress enhances macrophage recruitment into vascular and renal lesions by increasing the responsiveness of macrophages to chemoattractants. This novel mechanism contributes at least in part to accelerated atherosclerosis and kidney injury associated with dyslipidemia and diabetes in mice. Key Words: glutathione Ⅲ macrophage recruitment Ⅲ metabolic stress Ⅲ atherosclerosis Ⅲ inflammation M etabolic disorders such as hypercholesterolemia and diabetes are strongly associated with both macro-and microvascular diseases, a common feature of which is the recruitment of blood monocyte-derived macrophages to sites of vascular injury. Whereas most studies exploring the mechanisms underlying atherosclerosis and other vascular pathologies have focused on the impact of a dysregulated metabolism on the vasculature itself, a number of more recent studies suggest that metabolic disorders may also directly impact monocytes and alter their functionalities in ways that promote and accelerate the disease process. Phenotypic abnormalities in blood monocytes of diabetic patients have been reported, including altered metabolism, 1-3 phagocytosis, 4,5 and cytokine release. 6 -8 Furthermore, peritoneal macrophages isolated from either atherosclerosis-prone mice or diabetic mice show altered cytokine and chemokine responses compared with macrophages from healthy control mice. 9,10 However, it is not yet well-understood to what extent monocyte dysfunction induced by metabolic diseases contributes to macrophage recruitment and vascular diseases such as atherosclerosis.The recruitment of blood monocyte-derived macrophages into the vessel wall is co...
The morphological interrelationship between the central serotonergic and hypothalamic corticotropin-releasing factor (CRF) synthesizing systems was studied in the hypothalamic paraventricular nucleus (PVN) of colchicine pretreated male rats. The simultaneous immunocytochemical localization of the transmitter and peptide employed the peroxidase-antiperoxidase complex (PAP) technique using the silver-gold intensified (SGI) and non-intensified forms of the oxidized 3,3'-diaminobenzidine (DAB) chromogen. The paraventricular nucleus received a moderate serotonergic innervation as compared with other diencephalic structures. The distribution and arborization of serotonergic axons were more prominent in the parvocellular subnuclei than in the magnocellular units of the nucleus. Serotonin containing axons formed terminal bouton and en passant type synapses with dendrites and somata of parvocellular neurons. The immunocytochemical double labelling technique revealed the overlapping of serotonergic axons and CRF-immunoreactive neurons. Vibratome (40 micron) and semithin (1 micron) sections indicated that the interneuronal communication may take place on both dendrites and cell bodies of CRF-immunoreactive neurons. Ultrastructural analysis demonstrated that serotonin-containing terminals formed axo-dendritic and axo-somatic synapses with CRF-immunoreactive neurons. These findings indicate that the central serotonergic neuronal system can influence the function of the pituitary-adrenal endocrine axis via a direct action upon the hypophysiotrophic CRF synthesizing neurons.
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