Long-PDE4D degradation attenuates left ventricular cardiomyocyte hypertrophic remodelling

Abstract

Spatial compartmentalisation enables cyclic AMP (cAMP) to regulate distinct cellular functions, yet selectively targeting disease-associated signalling remains challenging. Phosphodiesterases constrain local cAMP responses, but conventional inhibitors offer limited isoform selectivity. Here we investigate whether targeted degradation of long phosphodiesterase-4D (PDE4D) isoforms can suppress pathological growth while preserving contractile function. Using adult rat and human ventricular cardiomyocytes and human myocardial slices, we show that the proteolysis-targeting chimera KTX-184 enhances compartmentalised cAMP signalling and attenuates hypertrophic remodelling. In rat cardiomyocytes, KTX-184 increases {beta}-adrenergic cAMP responses in the cytosol and at the plasma membrane, including T-tubule and crest regions, and enhances nuclear protein kinase A activity. In contrast, phospholamban- and ryanodine receptor-associated cAMP nanodomains, calcium transients and sarcomere shortening remain unchanged. KTX-184 prevents angiotensin II-induced hypertrophic remodelling, preserves T-tubule organisation and normalises hypertrophic marker expression. In human cardiomyocytes, it increases cytosolic cAMP responses and prevents overload-induced hypertrophy in myocardial slices. These findings identify long PDE4D isoforms as targets for spatially selective modulation of cAMP signalling and support targeted degradation as an approach to suppress cardiac hypertrophy without increasing contractility.

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BibTeX RIS

BibTeX

@misc{judina2026longpde4d,
  title = {{Long-PDE4D degradation attenuates left ventricular cardiomyocyte hypertrophic remodelling}},
  author = {A. Judina and Z. Shi and J. Fu and I. Sherstnev and V. Boichenko and J. Ling and M. Hussain and A. Zorn and Y. Y. Sin and H. Wang and A. Li and S. Korogodski and E. Torres and D. Stirling and K. Chan and C. Swindlehurst and I. Kibread and I. Black and S. Nicklin and G. S. Baillie and J. Gorelik},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.30.762532},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.30.762532v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Long-PDE4D degradation attenuates left ventricular cardiomyocyte hypertrophic remodelling
AU  - A. Judina
AU  - Z. Shi
AU  - J. Fu
AU  - I. Sherstnev
AU  - V. Boichenko
AU  - J. Ling
AU  - M. Hussain
AU  - A. Zorn
AU  - Y. Y. Sin
AU  - H. Wang
AU  - A. Li
AU  - S. Korogodski
AU  - E. Torres
AU  - D. Stirling
AU  - K. Chan
AU  - C. Swindlehurst
AU  - I. Kibread
AU  - I. Black
AU  - S. Nicklin
AU  - G. S. Baillie
AU  - J. Gorelik
PY  - 2026
DA  - 2026/10/30
PB  - bioRxiv
DO  - 10.64898/2026.10.30.762532
UR  - https://www.biorxiv.org/content/10.64898/2026.10.30.762532v1
AB  - Spatial compartmentalisation enables cyclic AMP (cAMP) to regulate distinct cellular functions, yet selectively targeting disease-associated signalling remains challenging. Phosphodiesterases constrain local cAMP responses, but conventional inhibitors offer limited isoform selectivity. Here we investigate whether targeted degradation of long phosphodiesterase-4D (PDE4D) isoforms can suppress pathological growth while preserving contractile function. Using adult rat and human ventricular cardiomyocytes and human myocardial slices, we show that the proteolysis-targeting chimera KTX-184 enhances compartmentalised cAMP signalling and attenuates hypertrophic remodelling. In rat cardiomyocytes, KTX-184 increases {beta}-adrenergic cAMP responses in the cytosol and at the plasma membrane, including T-tubule and crest regions, and enhances nuclear protein kinase A activity. In contrast, phospholamban- and ryanodine receptor-associated cAMP nanodomains, calcium transients and sarcomere shortening remain unchanged. KTX-184 prevents angiotensin II-induced hypertrophic remodelling, preserves T-tubule organisation and normalises hypertrophic marker expression. In human cardiomyocytes, it increases cytosolic cAMP responses and prevents overload-induced hypertrophy in myocardial slices. These findings identify long PDE4D isoforms as targets for spatially selective modulation of cAMP signalling and support targeted degradation as an approach to suppress cardiac hypertrophy without increasing contractility.
ER  -

Abstract

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