ACE2 Activation by Tripeptide IRW (Ile-Arg-Trp) Depends on the G Protein-Coupled Receptor 30 Signaling Cascade

Khushwant S. Bhullar, Hongbing Fan, Manal A. Nael, Khaled M. Elokely, Jianping Wu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

This study aimed to understand how specific cell-bound receptors influence ACE2 activation by IRW. Our results showed that G protein-coupled receptor 30 (GPR30), a 7-transmembrane domain protein, was involved in IRW-mediated ACE2 increase. IRW treatment (50 μM) significantly increased the GPR30 pool levels (3.2 ± 0.5 folds) (p < 0.001). IRW treatment also boosted the consecutive GEF (guanine nucleotide exchange factor) activity (2.2 ± 0.2 folds) (p < 0.001), and GNB1 levels (2.0 ± 0.5 folds) (p < 0.05), associated with the functional subunits of G proteins, in cells. These results were translated in hypertensive animal studies as well (p < 0.05), indicated by an increase in the aortal levels of GPR30 (p < 0.01); further experiments showed an increase in downstream PIP3/PI3K/Akt pathway activation following IRW treatment. The blockade of GPR30 by an antagonist and siRNA in cells abolished the ACE2-activating ability of IRW, as shown by the depleted levels of ACE2 mRNA (p < 0.001), protein levels in whole cells and membrane, angiotensin (1-7) (p < 0.01), and ACE2 promoter HNF1α (p < 0.05). Finally, the GPR30 blockade in ACE2-overexpressing cells using the antagonist (p < 0.01) and siRNA (p < 0.05) significantly depleted the innate cellular pool of ACE2, thus confirming the relationship between the membrane-bound GPR30 and ACE2. Overall, these results showed that the vasodilatory peptide IRW could activate ACE2 via the membrane-bound receptor GPR30.

Original languageEnglish
Pages (from-to)8071-8082
Number of pages12
JournalJournal of Agricultural and Food Chemistry
Volume71
Issue number21
DOIs
StatePublished - May 31 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.

Keywords

  • A7r5 cells
  • ACE2
  • ACE2 activation
  • GPCR
  • GPR30
  • IRW
  • hypertension

ASJC Scopus subject areas

  • General Chemistry
  • General Agricultural and Biological Sciences

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