Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling by Regulating Myocardial Tissue Angiotensin II

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Binh Y. Nguyen - , University of Manchester (Autor:in)
  • Fangchao Zhou - , University of Manchester (Autor:in)
  • Pablo Binder - , University of Manchester (Autor:in)
  • Wei Liu - , University of Manchester (Autor:in)
  • Susanne S. Hille - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Xiaojing Luo - , Institut für Pharmakologie und Toxikologie (Autor:in)
  • Min Zi - , University of Manchester (Autor:in)
  • Hongyuan Zhang - , University of Manchester (Autor:in)
  • Antony Adamson - , University of Manchester (Autor:in)
  • Fozia Z. Ahmed - , University of Manchester (Autor:in)
  • Sam Butterworth - , University of Manchester (Autor:in)
  • Elizabeth J. Cartwright - , University of Manchester (Autor:in)
  • Oliver J. Müller - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Kaomei Guan - , Institut für Pharmakologie und Toxikologie (Autor:in)
  • Elizabeth M. Fitzgerald - , University of Manchester (Autor:in)
  • Xin Wang - , University of Manchester (Autor:in)


BACKGROUND: Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. METHODS AND RESULTS: We established a CRISPR/CRISPR-associated protein 9–mediated global prolylcarboxylpeptidaseknockout and adeno-associated virus serotype 9–mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg per day) for 4 weeks, aiming to investigate the cardioprotective effect of prolylcarboxylpeptidase against hypertensive cardiac hypertrophy. Prolylcarboxylpeptidase expression was upregulated after 2 weeks of angiotensin II infusion and then became downregulated afterward in wild-type mouse myocardium, suggesting its compensatory function against angiotensin II stress. Moreover, angiotensin II–treated prolylcarboxylpeptidase-knockout mice showed aggravated cardiac remodeling and dampened cardiac contractility independent of hypertension. We also found that prolylcarboxylpeptidase localizes in cardiomyocyte lysosomes, and loss of prolylcarboxylpeptidase led to excessive angiotensin II levels in myocardial tissue. Further screening demonstrated that hypertrophic prolylcarboxylpeptidase-knockout hearts showed upregulated extracellular signal-regulated kinases 1/2 and downregulated protein kinase B activities. Importantly, adeno-associated virus serotype 9–mediated restoration of prolylcarboxylpeptidase expression in prolylcarboxylpeptidaseknockout hearts alleviated angiotensin II–induced hypertrophy, fibrosis, and cell death. Interestingly, the combination of adenoassociated virus serotype 9–mediated prolylcarboxylpeptidase overexpression and an antihypertensive drug, losartan, likely conferred more effective protection than a single treatment protocol to mitigate angiotensin II–induced cardiac dysfunction. CONCLUSIONS: Our data demonstrate that prolylcarboxylpeptidase protects the heart from angiotensin II–induced hypertrophic remodeling by controlling myocardial angiotensin II levels.


FachzeitschriftJournal of the American Heart Association
PublikationsstatusVeröffentlicht - 20 Juni 2023

Externe IDs

PubMed 37318028



  • hypertension, hypertrophy, lysosome, prolylcarboxylpeptidase, Myocytes, Cardiac/metabolism, Hypertension, Mice, Inbred C57BL, Ventricular Remodeling/physiology, Mice, Knockout, Animals, Myocardium/pathology, Angiotensin II/metabolism, Fibrosis, Mice