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

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in cardiovascular regulation.
• The activation mechanisms of ACE2 by specific peptides are not fully understood.
• G protein-coupled receptor 30 (GPR30) is implicated in various cellular signaling pathways.

Purpose of the Study:

• To investigate the role of cell-bound receptors in IRW-mediated ACE2 activation.
• To elucidate the involvement of GPR30 in the ACE2 activation pathway.
• To explore the downstream signaling events triggered by IRW and GPR30 interaction.

Main Methods:

• Treatment of cells and hypertensive animal models with IRW.
• Assessment of GPR30 pool levels, guanine nucleotide exchange factor (GEF) activity, and GNB1 levels.
• Analysis of downstream signaling pathways including PIP3/PI3K/Akt.
• Inhibition of GPR30 using an antagonist and small interfering RNA (siRNA).
• Quantification of ACE2 mRNA, protein levels, angiotensin (1-7), and HNF1α.

Main Results:

• IRW treatment significantly increased GPR30 levels, GEF activity, and GNB1 expression in cells.
• Hypertensive animal studies showed increased aortic GPR30 levels and activation of the PIP3/PI3K/Akt pathway post-IRW treatment.
• GPR30 blockade abolished IRW's ACE2-activating ability, reducing ACE2 mRNA, protein, angiotensin (1-7), and HNF1α.
• GPR30 blockade in ACE2-overexpressing cells depleted the cellular ACE2 pool, confirming the GPR30-ACE2 relationship.

Conclusions:

• The vasodilatory peptide IRW activates ACE2 through the membrane-bound receptor GPR30.
• GPR30 is a key mediator in the IRW-induced ACE2 activation pathway.
• Targeting the GPR30 receptor may offer a therapeutic strategy for conditions involving ACE2 regulation.