Hypercholesterolemia enhances oxidant production in mesenteric venules exposed to Ischemia/Reperfusion.
It has been shown that hypercholesterolemia (HCh) exaggerates the microvascular dysfunction that is elicited by ischemia and reperfusion (I/R). The objective of this study was to determine whether oxidants contribute to the exaggerated inflammatory responses and enhanced albumin leakage observed in HCh rat mesenteric venules exposed to I/R (10 minutes of ischemia and 30 minutes of reperfusion). Intravital videomicroscopy was used to quantify the number of adherent and emigrated leukocytes, albumin extravasation, platelet-leukocyte aggregation in postcapillary venules, and the degranulation of adjacent mast cells. Oxidation of the fluorochrome dihydrorhodamine 123 (DHR) was used to monitor oxidant production by venular endothelium. I/R was shown to elicit an increased DHR oxidation in venules of both control and HCh rats, with the latter group exhibiting a significantly larger response. Treatment with either oxypurinol or superoxide dismutase largely prevented the leukocyte recruitment, platelet-leukocyte aggregation, mast cell degranulation, and enhanced DHR oxidation elicited by I/R in HCh rats. The enhanced albumin leakage was reduced by superoxide dismutase but not by oxypurinol. These results indicate that HCh amplifies the oxidant stress elicited by I/R and that interventions that blunt the oxidant stress effectively attenuate the leukocyte, platelet, and mast cell activation that result from I/R.
Department of Molecular and Cellular Physiology, Center of Excellence in Arthritis and Rheumatology, Louisiana State University Medical Center, Shreveport, LA 71130-3932, USA.
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Kurose
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Wolf
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MB
Grisham
D N
DN
Granger
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D010117:Oxypurinol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D012235:Rhodamines / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology
D000418:Albumins; D004791:Enzyme Inhibitors; D016877:Oxidants; D012235:Rhodamines; C058319:dihydrorhodamine 123; D013482:Superoxide Dismutase; D010117:Oxypurinol