# Dapagliflozin improves diabetic cardiomyopathy by suppressing the STAT3-YY1 signaling axis in cardiac fibroblasts

## TL;DR

Dapagliflozin reduces heart damage in diabetes by blocking a specific signaling pathway in heart cells, unrelated to its usual mechanism.

## Contribution

Dapagliflozin's anti-fibrotic effects in diabetic cardiomyopathy are shown to be independent of SGLT2 inhibition.

## Key findings

- Dapagliflozin inhibits STAT3 phosphorylation and YY1 nuclear translocation in cardiac fibroblasts.
- Dapagliflozin reduces cardiac fibrosis and dysfunction in diabetic mice.
- SGLT2 knockdown does not inhibit cardiac fibroblast activation in diabetic mice.

## Abstract

Cardiac fibroblast (CF) proliferation and activation drive cardiac fibrosis and heart failure. Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, ameliorates diabetic cardiomyopathy (DCM). We investigated whether DAPA exerts anti-fibrotic and cardioprotective effects on DCM by directly suppressing CF proliferation and activation independent of SGLT2 inhibition.

CFs were isolated from mouse hearts. Mouse cardiac function and fibrosis were investigated using histological analysis, western blotting, and echocardiography. Additionally, genetic loss-of-function studies were conducted in vitro by small interfering RNA silencing and in vivo by lentivirus-mediated gene knockdown.

Compared with high-glucose-treated neonatal rat CFs, genetic loss-of-function of signal transducer and activator of transcription 3 (STAT3) or pretreatment with DAPA dramatically inhibited STAT3 phosphorylation and Yin Yang 1 (YY1) nuclear translocation, alleviated CF proliferation and activation, and reduced fibrosis. In diabetic db/db mice, administration of DAPA remarkably ameliorated diabetes-induced STAT3 activation, YY1 nuclear translocation, CF proliferation and activation, and reduced cardiac fibrosis and dysfunction. These in vitro and in vivo effects of DAPA were ameliorated by colivelin TFA, a potent activator of STAT3. Intriguingly, knockdown of SGLT2 did not have an inhibitory effect on CF proliferation and activation in db/db mice.

DAPA reduces cardiac fibrosis and DCM. This may, at least in part, be attributable to the repression of the STAT3-YY1 signaling axis-mediated CF proliferation and activation, independent of SGLT2 inhibition.