Role of angiotensin II in ischemia/reperfusion‐induced leukocyte‐endothelium interactions in the colon

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Abstract
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.
Funding Information
  • Svenska Forskningsrådet Formas (2001-6576, 2002-955, 2002-8012, 2003-4661)
  • Crafoordska Stiftelsen
  • Einar och Inga Nilssons Stiftelse för Kirurgiforskning och Forskning inom Jordbruket
  • Greta och Johan Kocks stiftelser
  • Magnus Bergvalls Stiftelse
  • Ruth och Richard Julins Stiftelse
  • Allmänna Sjukhusets i Malmö Stiftelse för Bekämpande av Cancer
  • Royal College of Surgeons of England