# Sustained HIF activation in adult cardiomyocytes show transient beneficial effect in murine HFpEF model

## TL;DR

Sustained HIF activation in adult heart cells shows temporary benefits in a mouse model of heart failure with preserved ejection fraction.

## Contribution

This study demonstrates the transient beneficial effects of sustained HIF activation in a murine HFpEF model.

## Key findings

- VHL-MCM mice showed increased capillary density and HIF-target gene expression in normal aging.
- VHL-MCM mice exhibited preserved global longitudinal strain in the HFpEF model at 12 weeks.
- There was a trend toward reduced fibrosis and increased capillary density in VHL-MCM mice under HFpEF conditions.

## Abstract

Hypoxia-inducible factor (HIF) signalling influences cardiomyocyte differentiation, maturation, and metabolic adaptation under pathological conditions. HIF-Prolyl hydroxylase domain (HIF-PH) inhibitors, which target this pathway, have been introduced for the treatment of renal anaemia. Their precise effect or safety on cardiac function remains unclear because their pharmacokinetics and distribution are not well-understood. This study aimed to examine HIF signalling activation in adult cardiomyocytes (CMs).

We used tamoxifen (TAM)-inducible, CM-specific von Hippel–Lindau (VHL) knockout (VHL-MCM) mice to activate CM HIF signalling. Then we subjected the mice to normal ageing or high-fat diet (HFD) and L-NAME feeding, a murine model of heart failure with preserved ejection fraction (HFpEF). In normal ageing group, there was no difference in the echocardiographic parameters or tissue fibrosis between VHL-MCM and control mice. VHL-MCM mice exhibited significantly increased capillary density and higher expression levels of HIF-target genes (P = 0.0248, two-way ANOVA). Under HFD + L-NAME treatment, VHL-MCM mice showed transient but significantly preserved global longitudinal strain (GLS) at 12 weeks post-TAM injection compared to controls (P = 0.0284, two-way ANOVA). Sirius red staining indicated a trend towards reduced whole-heart and interstitial fibrosis with significant increase in capillary density in VHL-MCM mice.

Sustained HIF signalling activation in adult CM does not impair the cardiac structure and function in normal ageing process and shows transient yet beneficial effect in murine HFpEF model.

Graphical Abstract