Hypercholesterolemia Enhances Oxidant Production in Mesenteric Venules Exposed to Ischemia/Reperfusion

From the Department of Molecular and Cellular Physiology, Center of Excellence in Arthritis and Rheumatology, Louisiana State University Medical Center, Shreveport.

Correspondence to Dr D. Neil Granger, Department of Molecular and Cellular Physiology, LSU Medical Center, 1501 Kings Hwy, PO Box 33932, Shreveport, LA 71130-3932. E-mail dgrang{at}lsumc.edu

Abstract—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.

Key Words: vascular permeability • platelet aggregation • mast cell degranulation • leukocyte–endothelial cell adhesion

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