Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 1.
doi: 10.1111/bph.70094. Online ahead of print.

Stabilisation of PRCP by deubiquitinase-targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy

Fangchao Zhou  1 , Jun Xia  2 , Yingjuan Liu  1 , Wenqi He  1 , Hongyuan Zhang  1 , Bernard D Keavney  1 , Min Zi  1 , Binh Y Nguyen  1 , Tamer M A Mohamed  3 , Jessica M Miller  3 , Riham R E Abouleisa  3 , Susanne S Hille  4   5 , Elizabeth J Cartwright  1 , Oliver J Müller  4   5 , Honglin Xu  1 , Sam Butterworth  2 , Xin Wang  1
Affiliations

Stabilisation of PRCP by deubiquitinase-targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy

Fangchao Zhou et al. Br J Pharmacol. .

Abstract

Background and purpose: Autophagy is essential for cellular homeostasis, and its impairment contributes to cardiac hypertrophy. Modulating autophagy has shown potential in treating pathological hypertrophy. Prolylcarboxypeptidase (PRCP), a lysosomal enzyme that hydrolyzes angiotensin II to Ang1-7, has an unclear role in cardiac autophagy and hypertrophy. This study explores PRCP's function in regulating autophagy under hypertrophic stress and its potential as a therapeutic target.

Experimental approach: Transverse aortic constriction (TAC) was used to induce hypertrophy in mice. PRCP-knockout (PRCPKO) mice were generated using CRISPR/Cas9, while PRCP was overexpressed in the heart using adeno-associated virus 9. Cardiac function was evaluated via echocardiography and histological analysis. Autophagy markers were assessed by immunostaining, electron microscopy, and protein expression. In vitro, PRCP expression was manipulated in H9c2 cells. A novel DUBTAC compound was also synthesized to stabilize PRCP, and its protective effects were tested in H9c2 cells and hESC-derived cardiomyocytes under isoprenaline-induced stress.

Key results: PRCPKO mice developed more severe cardiac hypertrophy, fibrosis, and diastolic dysfunction after TAC. These mice showed reduced autophagosome formation and decreased expression of autophagy-related proteins WDR1 and WIPI1. In contrast, PRCP overexpression mitigated hypertrophy and preserved autophagy. Mechanistically, PRCP regulated autophagy via the interaction of WDR1 with WIPI1. Stabilizing PRCP with DUBTAC prevented its degradation and maintained autophagy under hypertrophic conditions.

Conclusions and implications: PRCP is a previously unrecognized regulator of autophagy in the heart. Enhancing PRCP expression or stabilizing it pharmacologically via DUBTAC represents a novel and effective therapeutic approach for managing pathological cardiac hypertrophy and improving cardiac health.

Keywords: DUBTAC; Prolylcarboxypeptidase; autophagy; cardiac hypertrophy.

PubMed Disclaimer

References

REFERENCES

    1. Alexander, S. P., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Abbracchio, M. P., Alexander, W., Al‐Hosaini, K., Bäck, M., Barnes, N. M., Bathgate, R., … Ye, R. D. (2023). The Concise Guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. British Journal of Pharmacology, 180(Suppl 2), S23–S144. https://doi.org/10.1111/bph.16177
    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Ostrom, R., Papapetropoulos, A., … Wong, S. S. (2023b). The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. British Journal of Pharmacology, 180(Suppl 2), S289–S373. https://doi.org/10.1111/bph.16181
    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Amarosi, L., Anderson, C. M. H., Beart, P. M., Broer, S., Dawson, P. A., Gyimesi, G., Hagenbuch, B., Hammond, J. R., Hancox, J. C., … Verri, T. (2023a). The Concise Guide to PHARMACOLOGY 2023/24: Transporters. British Journal of Pharmacology, 180(Suppl 2), S374–S469. https://doi.org/10.1111/bph.16182
    1. Aragon‐Herrera, A., Feijóo‐Bandín, S., Otero Santiago, M., Barral, L., Campos‐Toimil, M., Gil‐Longo, J., Costa Pereira, T. M., García‐Caballero, T., Rodríguez‐Segade, S., Rodríguez, J., Tarazón, E., Roselló‐Lletí, E., Portolés, M., Gualillo, O., González‐Juanatey, J. R., & Lago, F. (2019). Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochemical Pharmacology, 170, 113677. https://doi.org/10.1016/j.bcp.2019.113677
    1. Ayyadevara, S., Mercanti, F., Wang, X., Mackintosh, S. G., Tackett, A. J., Prayaga, S. V., Romeo, F., Shmookler Reis, R. J., & Mehta, J. L. (2016). Age‐ and hypertension‐associated protein aggregates in mouse heart have similar proteomic profiles. Hypertension, 67, 1006–1013. https://doi.org/10.1161/HYPERTENSIONAHA.115.06849