PubMed · 5025679
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K W Diederich, M N Levy. 1972. Pacemaker synchronization in atrioventricular dissociation.. https://pubmed.ncbi.nlm.nih.gov/5025679/
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Loss of the modulatory role of the endothelium may be a critical initial factor in the development of diabetic vascular diseases. Exposure of human aortic endothelial cells (HAECs) to high glucose (30 or 44 mmol/l) for 7-10 days significantly increased the release of superoxide anion in response to the calcium ionophore A23187. Nitrate, a breakdown product of peroxynitrite (ONOO(-)), was substantially increased in parallel with a decline in cyclic guanosine monophosphate (GMP). Using immunochemical techniques and high-performance liquid chromatography, an increase in tyrosine nitration of prostacyclin (PGI(2)) synthase (PGIS) associated with a decrease in its activity was found in cells exposed to high glucose. Both the increase in tyrosine nitration and the decrease in PGIS activity were lessened by decreasing either nitric oxide or superoxide anion, suggesting that ONOO(-) was responsible. Furthermore, SQ29548, a thromboxane/prostaglandin (PG) H(2) (TP) receptor antagonist, significantly reduced the increased endothelial cell apoptosis and the expression of soluble intercellular adhesion molecule-1 that occurred in cells exposed to high glucose, without affecting the decrease in PGIS activity. Thus, exposure of HAECs to high glucose increases formation of ONOO(-), which causes tyrosine nitration and inhibition of PGIS. The shunting of arachidonic acid to the PGI(2) precursor PGH(2) or other eicosanoids likely results in TP receptor stimulation. These observations can explain several abnormalities in diabetes, including 1) increased free radicals, 2) decreased bioactivity of NO, 3) PGI(2) deficiency, and 4) increased vasoconstriction, endothelial apoptosis, and inflammation via TP receptor stimulation.
A large number of constituents, such as growth factors, cytokines, and vasoregulatory molecules, contribute a network of cellular interactions to atherosclerotic lesions, and current evidence suggests that granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of these constituents. We conducted this study to determine whether GM-CSF has an effect on the fate and function of macrophages. We examined the effect of GM-CSF on macrophages in vitro with a highly inducible HL60 subclone (HL60/DU-1) that we recently established. HL60 cells have been reported to preserve functional GM-CSF receptors, but a GM-CSF allele was rearranged and partially deleted. HL60/DU-1 cells were devoid of GM-CSF immunoreactivity and of autocrine stimulation of GM-CSF. HL60/DU-1 cells fated to die soon after terminal differentiation of macrophages by 1, 25-dihydroxy vitamin D(3) treatment. We found cell death to be mediated mainly by necrosis, not apoptosis, as confirmed by DNA fragmentation in agarose gel electrophoresis, morphological observation under a fluorescence microscope, and assay of lactate dehydrogenase release. Exogeneously administered GM-CSF rescued cells from necrotic death and caused them to survive and generate superoxide anions. We also conducted immunohistochemical analysis on an atherosclerotic human artery. Macrophages, endothelial cells, and smooth muscle cells were found to be GM-CSF positive in an atherosclerotic lesion. In summary, GM-CSF, which is produced by macrophages, endothelial cells, and smooth muscle cells, is thought to act in an autocrine and a paracrine fashion as a necrosis-inhibiting factor against arterial macrophages. This unique function may play an important role in ensuring survival and promoting function in atherosclerotic lesions.
The pressure pulse does not have the same amplitude in central and peripheral arteries, but it is amplified toward the periphery; the degree of this amplification depends principally on wave reflection. Despite the conventional clinical and epidemiological focus on peripheral pressures, the most physiologically relevant pressures for both cardiac and vascular effects are central pressures. The reflected wave contributes differently in the configuration of the peripheral and central pressure waveform. Therefore, we hypothesized that agents that alter wave reflections could have an unequal effect on central and peripheral pressures in hypertensive patients. Thus, the effect of caffeine was investigated in 10 hypertensive subjects according to a randomized, placebo-controlled, double-blind, crossover design. Central aortic pressures and wave reflection were assessed with applanation tonometry and pulse wave analysis. After caffeine, augmentation index and augmented pressure increased by 4.6%, (P<0.005) and 5.7 mm Hg (P<0.001), respectively, indicating increased effect of wave reflection from the periphery. The increase in aortic systolic pressure was greater compared with that in radial artery pressure at 30 minutes (25%) and marginally greater at 60 minutes (21%). Furthermore, the increase in aortic pulse pressure was greater at 30 and 60 minutes (34% and 40%, respectively). The intensified reflected wave after caffeine was largely responsible for the disparate effect between central and peripheral pressures by boosting the peak of the central and not of the peripheral waveform. This study shows that pressure-altering agents might affect central pressures more than is apparent from the corresponding upper limb values because of the concomitant changes in wave reflection.