# Cardiac fibrosis induced by high‐fat diet in ApoE‐deficient male mice is exacerbated by genetic deletion of PACAP–PAC1 signaling

## TL;DR

Deleting the PACAP–PAC1 signaling pathway worsens heart fibrosis in mice fed a high-fat diet.

## Contribution

The study reveals that PACAP–PAC1 signaling mitigates metabolic stress-induced cardiac fibrosis in ApoE-deficient mice.

## Key findings

- Deleting PACAP or PAC1 in ApoE-deficient mice significantly increases cardiac fibrosis under a high-fat diet.
- PACAP's antifibrotic effect depends on the PAC1 receptor and occurs only under metabolic stress.
- PAC1 receptor agonists may help reduce cardiac fibrosis caused by chronic high-fat diets.

## Abstract

Cardiac fibrosis is characterized by an excessive accumulation of extracellular matrix proteins and occurs in a variety of cardiac diseases, such as the highly prevalent syndrome heart failure with preserved ejection fraction (HFpEF) and other cardiac disorders. Interstitial fibrosis has been identified as a central pathophysiological factor induced and maintained by metabolic stress and chronic inflammation. Considering the limited treatment options for cardiac fibrosis, new therapeutic targets are urgently needed. Mounting evidence for the cardioprotective effects of the neuropeptide pituitary adenylate cyclase‐activating peptide (PACAP) provides a rationale to elucidate its role and that of its receptor PAC1 in metabolic stress‐mediated cardiac fibrosis. Metabolic stress was induced by feeding a cholesterol‐enriched diet (CED) to PACAP−/−/ApoE−/−, PAC1−/−/ApoE−/− and ApoE−/− mice and cardiac tissue subjected to analyses of fibrosis. Under CED feeding, a statistically significant (p < .001) increase in myocardial fibrosis was observed in PACAP−/−/ApoE−/− and PAC1−/−/ApoE−/− compared to ApoE−/− mice. These findings suggest a role for PACAP signaling in the mitigation of metabolically induced cardiac fibrosis. The antifibrotic effect of PACAP is dependent on the expression of the PAC1 receptor and only emerges under metabolic stress conditions. PAC1 receptor agonists may have the potential to attenuate metabolically triggered cardiac fibrosis arising after a chronic high‐fat diet.