# Implication of intracellular chloride channel in extracellular matrix remodeling in pressure‐overloaded mice and patients with dilated cardiomyopathy

## TL;DR

This study explores how intracellular chloride channels contribute to heart disease by analyzing their role in mice and human heart cells.

## Contribution

The novel contribution is identifying CLICs as potential therapeutic targets for cardiac hypertrophy and failure through their role in extracellular matrix remodeling.

## Key findings

- CLIC1, CLIC4, and CLIC5 expression increased in mice with cardiac hypertrophy and in patients with dilated cardiomyopathy.
- CLICs were linked to pathways involved in extracellular matrix remodeling and actin cytoskeleton regulation.
- These findings suggest CLICs may be viable targets for treating heart failure.

## Abstract

Chloride intracellular channels (CLICs) are important in cardiac cellular physiology. We aimed to determine the pathophysiological roles of CLICs in the heart. For this, we analyzed CLIC expression in cardiomyocytes in a mouse transverse aortic constriction (TAC) model to induce cardiac hypertrophy and failure, as well as in ventricular myocytes from patients with dilated cardiomyopathy (DCM) using single‐cell RNA‐sequencing. Single‐ventricular myocytes were isolated from the left ventricular free wall of C57BL/6J mice after TAC (pre‐TAC; Day 3 post‐TAC; and Weeks 1, 2, 4, and 8 post‐TAC). Gene expression was compared with data from sham controls. In mice, CLIC1 and CLIC4 expression significantly increased in Day 3 and Weeks 1, 2, and 4 post‐TAC. CLIC5 expression showed an increase during all phases. Kyoto Encyclopedia of Genes and Genomes pathway analysis for genes associated with CLIC1, CLIC4, and CLIC5 revealed a strong association between focal adhesion activation and actin cytoskeleton regulation pathways linked to extracellular matrix (ECM) remodeling. CLIC1 and CLIC4 expression was also higher in cells from patients with DCM. Single‐cell RNA‐sequencing revealed the possible role of CLICs in myocardial ventricular remodeling linked to ECM, proposing their potential as therapeutic targets for cardiac hypertrophy and failure.