Smooth Muscle Silent Information Regulator 1 Contributes to Colitis in Mice

TL;DR

This study shows that overexpression of SIRT1 in smooth muscle cells worsens colitis in mice by impairing intestinal recovery.

Contribution

The study identifies a novel signaling axis involving cZFP609 and HIF-1α linking smooth muscle cells to intestinal epithelium in colitis.

Findings

Smooth-muscle-specific SIRT1 overexpression disrupts baseline intestinal architecture.

Overexpression of SIRT1 impairs recovery after DSS-induced intestinal injury.

SIRT1 in smooth muscle cells inhibits HIF-1α nuclear translocation via cZFP609, affecting epithelial regeneration.

Abstract

Smooth muscle cells (SMCs) are an essential component of the intestine, play an important role to maintain intestine structure, and produce peristaltic and segmentation movements. The silent information regulator 1 (SIRT1) has a dual role along with possible mechanisms in the different experimental models of inflammatory bowel disease (IBD). However, very little is known about other putative roles that overexpression of SIRT1 in SMCs may have. Here, we explored the role of SMC SIRT1 in colonic mucosa regeneration and recovery after DSS-induced colitis. We showed that smooth-muscle-specific SIRT1 transgene (Sirt1-Tg) mice have abnormal baseline intestinal architecture. The overexpression of SIRT1 impaired the recovery after DSS-induced injury. Furthermore, we showed that smooth-muscle SIRT1 affected the intestinal epithelial regeneration after damage by releasing cZFP609, which inhibited the hypoxia-inducible factor (HIF)-1α nuclear translocation. Together, we identify an important signaling axis cZFP609-HIF-1α linking SMCs and intestinal epithelium, which is involved in colitis development.

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