Reduced severity in a mouse model of colitis with angiotensin converting enzyme inhibition

Abstract

Background. Both human ulcerative colitis (UC) and an established mouse model of colitis (oral dextran sodium sulfate (DSS)) show ulcerative lesions attributable to epithelial cell (EC) apoptosis. ECs are known to express high levels of angiotensin converting enzyme (ACE). Recent studies indicate that administering ACE inhibitors (ACE-I) decreases apoptosis in diverse epithelial tissues. Also, we have found that ACE-I suppress basal levels of EC apoptosis in the small intestine. We hypothesized that ACE-I may exert a similar anti-apoptotic effect in the colon and thus reduce the severity of colitis. Methods. Male C57BL/6 mice drank 2.5% DSS in water for either 3 or 7 days plus 1 day of plain water. Mice received daily enalaprilat (0.015 mg/day, intraperitoneal) injection ( n = 6 at each time point, ACE-I) or saline injection ( n = 6 at each time point, Saline). Body weight and clinical severity of colitis were recorded. After the specified number of days, mice were euthanized and colonic epithelium was harvested. Blinded histologic grading of colitis used standard scores. Reverse transcriptase real-time PCR assessed mRNA levels of ACE. Epithelial apoptosis was assessed by flow cytometry with Annexin V/Propidium Iodide. Data are mean ± SD ( t-test). Results. ACE-I reduced body weight loss (16.6 ± 2.7%) versus Saline (23.7 ± 4.2%, P < 0.01) after a week of DSS, and delayed onset of heme-positive stools (4.8 ± 0.8 days versus 3.7 ± 1.0 days, P < 0.05). ACE-I mice also showed significantly improved histologic colitis scores versus Saline after 1 week (11.8 ± 1.5 versus 14.7 ± 1.4, P < 0.01), at which time point mucosal ACE mRNA levels were reduced in ACE-I versus Saline mice (expressed relative to beta-actin, 0.08 ± 0.1 versus 4.1 ± 4.7, P < 0.05). Flow cytometry showed a trend at 3 days toward decreased apoptosis in ACE-I colons (Saline, 15.9 ± 12.7% apoptotic versus ACE-I, 5.3 ± 5.1%, p = ns). Conclusions. ACE inhibition improved DSS-induced mouse colitis clinically and histologically. Enalaprilat reduced colonic tissue ACE expression after 1 week. It appears ACE-I may reduce colonic epithelial ulcers through a reduction in apoptosis, but we were unable to prove this point. This study suggests that ACE-I therapy may have a future potential benefit for inflammatory bowel disease.