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Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition
Ariel U Spencer1, Hua Yang, Emir Q Haxhija
1Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
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.
Insights
Angiotensin converting enzyme inhibition (ACE-I) significantly reduced ulcerative colitis severity and colonic epithelial cell apoptosis in a mouse model. ACE-I treatment lowered pro-apoptotic factors, suggesting a therapeutic benefit for colitis.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Ulcerative colitis involves increased epithelial cell apoptosis and tumor necrosis factor alpha (TNF-alpha).
- Angiotensin converting enzyme (ACE) promotes apoptosis, while ACE inhibition (ACE-I) reduces it in vitro.
- ACE-I may offer a therapeutic strategy for inflammatory bowel diseases like ulcerative colitis.
Purpose of the Study:
- To investigate the efficacy of ACE-I (enalaprilat) in reducing colonic epithelial cell apoptosis and colitis severity.
- To evaluate the impact of ACE-I on key apoptosis-related gene expression in a dextran sulfate sodium (DSS)-induced colitis model.
Main Methods:
- Mice were induced with DSS to model colitis.
- Experimental groups received daily ACE-I (enalaprilat) or placebo treatment.
- Colitis severity, epithelial apoptosis rates, and expression of TNF-alpha, Bcl-2, and Bax were assessed.
Main Results:
- ACE-I treatment significantly improved clinical outcomes and reduced histopathologic colitis scores.
- Epithelial cell apoptosis rates were dramatically reduced in the ACE-I group.
- ACE-I treatment led to significantly lower TNF-alpha mRNA levels and a reduced Bax to Bcl-2 ratio.
Conclusions:
- ACE-I effectively reduces the severity of DSS-induced colitis in mice.
- ACE-I mitigates colonic epithelial cell apoptosis, potentially through modulation of TNF-alpha and apoptosis-regulating proteins.
- These findings support the potential of ACE-I as a therapeutic agent for ulcerative colitis.
