Angiotensin II type 1 receptors and the intestinal microvascular dysfunction induced by ischemia and reperfusion.
The acute phase of intestinal ischemia-reperfusion (I/R) injury is mediated by leukocytes and is characterized by oxidative stress and blood cell recruitment. Upregulation of angiotensin II type 1 receptors (AT1-R) has been implicated in the pathogenesis of conditions associated with oxidative stress. The AT1-R-antagonist Losartan (Los) attenuates leukocyte recruitment following I/R. However, the role of AT1-R in intestinal I/R injury and the associated platelet-leukocyte interactions remains unclear. The objective of this study was to define the contribution of AT1-R to I/R-induced blood cell recruitment in intestinal venules. Leukocyte and platelet adhesion were quantified by intravital microscopy in the small bowel of C57Bl/6 [wild-type (WT)] mice exposed to sham operation or 45 min of ischemia and 4 h of reperfusion. A separate WT group received Los for 7 days before gut I/R (WT-I/R + Los). AT1-R bone marrow chimeras that express AT1-R on the vessel wall but not blood cells also underwent I/R. Platelet and leukocyte adhesion as well as AT1-R expression in the gut microvasculature were significantly elevated after I/R. All of these responses were attenuated in the WT-I/R + Los group, compared with untreated I/R mice. A comparable abrogation of I/R-induced blood cell adhesion was noted in AT1-R bone marrow chimeras. I/R-induced platelet adhesion was unaltered in mice overexpressing Cu,Zn-SOD or mice deficient in NAD(P)H oxidase. These data suggest that although gut I/R upregulates endothelial expression of AT1-R, engagement of these angiotensin II receptors on blood cells is more important in eliciting the prothrombogenic and proinflammatory state observed in postischemic gut venules, through a superoxide-independent pathway.
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, 71130, USA.
Thomas
T
Petnehazy
Dianne
D
Cooper
Karen Y
KY
Stokes
Janice
J
Russell
Katherine C
KC
Wood
D Neil
DN
Granger
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000378:metabolism* / Q000473:pathology*; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse