Role of angiotensin II in ischemia/reperfusion-induced leukocyte-endothelium interactions in the colon.
The aims of the present study were to determine the effects and mechanisms of angiotensin II (Ang II) on leukocyte-endothelium interactions and the role of Ang II in a novel model of ischemia/reperfusion (I/R) in the mouse colon. Ang II dose-dependently increased leukocyte rolling and adhesion in colonic venules. Importantly, Ang II-induced leukocyte rolling was completely inhibited by immunoneutralization of P-selectin, and leukocyte adhesion was abolished in lymphocyte function antigen-1 (LFA-1)-deficient mice. The P-selectin-dependent rolling was found to be a precondition for the subsequent LFA-1-dependent leukocyte adhesion. Moreover, Ang II-induced leukocyte responses involved generation of reactive oxygen species and up-regulation of CXC chemokines. Notably, CXC chemokines, but not Ang II, stimulated leukocyte chemotaxis in vitro. I/R increased gene expression of angiotensin converting enzyme (ACE) in the colon and plasma concentrations of Ang II. Inhibition of ACE and the type 1 angiotensin (AT1) receptor significantly decreased the I/R-induced leukocyte adhesion. Taken together, these novel findings demonstrate that Ang II exerts potent pro-inflammatory effects in the colonic microcirculation and that inhibition of Ang II expression or function protects against I/R-induced leukocyte responses in the colon. Thus, it is suggested that Ang II is a major target to control pathological inflammation in the colon.
Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
Amjid A
AA
Riaz
Yusheng
Y
Wang
Rene
R
Schramm
Tohru
T
Sato
Michael D
MD
Menger
Bengt
B
Jeppsson
Henrik
H
Thorlacius
D000493:Allopurinol / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000473:pathology; D002216:Captopril / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D003106:Colon / Q000098:blood supply*; D003250:Constriction; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology*; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation; D007511:Ischemia / Q000503:physiopathology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D017538:Mesenteric Artery, Superior; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D018925:Chemokines; D019007:P-Selectin; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D000493:Allopurinol; D002216:Captopril; D013482:Superoxide Dismutase; D019808:Losartan