Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition.
Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-alpha). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-alpha expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-alpha, Bcl-2, and Bax expression. TNF-alpha mRNA was significantly lower with ACE-I treatment compared to placebo at every time point, as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.
Spencer
Ariel U
AU
Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Yang
Hua
H
Haxhija
Emir Q
EQ
Wildhaber
Barbara E
BE
Greenson
Joel K
JK
Teitelbaum
Daniel H
DH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003106:Colon / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D015773:Enalaprilat / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005434:Flow Cytometry; D007413:Intestinal Mucosa / Q000098:blood supply / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D016264:Dextran Sulfate; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat