Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

•A peptide was discovered that disrupts HSP20–phosphodiesterase 4D (PDE4D) complex formation.•HSP20–PDE4D complex disruption reversed hypertrophic-induced changes in electrical signalling in human cardiac myocytes.•HSP20–PDE4D complex disruption attenuated the physiological response to pressure/volume overload.•This physiological response normally results in an increase in cardiac myocyte size.•Cardiac fibrosis was reduced in mice following treatment with the HSP20–PDE4D disruptor peptide. Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling.