# Evaluation of myocardial classic and alternative pathways of the renin-angiotensin system in cholestasis-induced cardiac injury: A time-course experimental study in rats

## TL;DR

This study explores how the renin-angiotensin system changes in the hearts of rats with cholestasis over six weeks, revealing potential new treatment targets for related heart damage.

## Contribution

The study provides new insights into the time-dependent changes in classic and alternative RAS pathways in cholestasis-induced cardiac injury.

## Key findings

- Classic RAS components like ACE increased after week 4, while AT1R and AT2R were down-regulated.
- Alternative RAS components like ACE2 and Mas receptor showed a biphasic pattern, with up-regulation in late stages.
- The alternative RAS pathway may act as a compensatory mechanism in late-stage cholestasis.

## Abstract

Cholestasis, characterized by impaired bile flow and elevated bile acid levels, can lead to cardiac dysfunction, termed Cholecardia syndrome. The pathophysiology of cholestasis-induced cardiac injury involves direct and indirect effects of bile acids through various molecular pathways. However, the role of the renin-angiotensin-aldosterone system (RAS), modulated by bile acids, remains unclear.This study aimed to investigate alterations in the expression of classic and alternative RAS components in the myocardium of rats with obstructive cholestasis in a six-week period.

Forty-two male Wistar rats (8 weeks old, 250 ± 30 g) were randomly assigned to seven groups (n=6 per group): one sham-operated group and six bile duct ligation (BDL) groups, sacrificed at weekly intervals from 1 to 6 weeks post-surgery. Quantitative RT-PCR was used to analyze cardiac RAS component expression. Biochemical and histopathological evaluations were conducted to assess disease progression.

In the classic RAS pathway, myocardial angiotensin-converting enzyme (ACE) expression increased after week 4 of BDL, while angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) were significantly down-regulated in this period. In contrast, the alternative RAS pathway components, including ACE2 and the Mas receptor, exhibited a biphasic expression pattern in the myocardium, with down-regulation at week 3 followed by significant up-regulation at weeks 5–6.

The findings reveal distinct alterations in RAS pathways during cholestasis-induced cardiac injury. The alternative RAS pathway may play a compensatory role in late-stage cholestasis, highlighting potential therapeutic targets for Cholecardia syndrome and cirrhotic cardiomyopathy.