Long-PDE4D degradation attenuates left ventricular cardiomyocyte hypertrophic remodelling

Targeted degradation of long PDE4D isoforms with KTX-184 enhances compartmentalised cAMP signalling and attenuates hypertrophic remodelling in adult rat and human ventricular cardiomyocytes.

• Why it matters: Local cAMP control is crucial for distinct cardiac functions, but conventional PDE inhibition lacks isoform selectivity and can disrupt contractile signalling during disease-associated growth.
• What they did: Adult rat and human ventricular cardiomyocytes and human myocardial slices were treated with the proteolysis-targeting chimera KTX-184, then assessed for compartment-specific cAMP responses, PKA activity, calcium transients, and hypertrophic markers.
• The result: KTX-184 increased β-adrenergic cAMP responses and nuclear PKA activity while leaving phospholamban- and ryanodine receptor-associated nanodomains, calcium transients, and sarcomere shortening unchanged, and it prevented angiotensin II- and overload-induced hypertrophy.

AI summary of the abstract · may contain errors · not medical advice · read the paper.