Tripeptide IRW increases epithelial cadherin (E-cadherin) level via angiotensin converting enzyme 2 (ACE2) axis

The tripeptide IRW has been shown to upregulate E-cadherin expression in the aortas of spontaneously hypertensive rats (SHRs). E-cadherin, a transmembrane glycoprotein, plays a key role in cell–cell adhesion, migration, proliferation, survival, and differentiation. Given the mechanistic function of angiotensin-converting enzyme 2 (ACE2) in IRW’s blood pressure regulation, this study aimed to explore the role of ACE2 axis in the regulation of E-cadherin by IRW. IRW increased E-cadherin expression, reduced zinc finger protein SNAI1 (Snail1), and intracellular Ca 2+ concentration in both A7r5 rat aortic vascular small muscle cells and the aorta of SHRs. However, calcium release-activated calcium modulator 1 (Orai 1) expression was reduced only in A7r5 cells, but not in SHRs. Co-treatment of IRW with angiotensin II (Ang II), ACE2 knockdown or Mas receptor (MasR) antagonist abolished the ability of IRW to increase E-cadherin expression in A7r5 cells. Tamoxifen increased E-cadherin expression in A7r5 cells without affecting ACE2 levels. Our findings suggest that the ACE2 axis and Orai1/Ca2 + pathway play a key role in the regulation of E-cadherin by IRW. • Tripeptide IRW upregulated E-cadherin in vascular smooth muscle cells and SHR aortas. • IRW suppresses cell migration, reducing Snail1 expression and intracellular Ca²⁺ levels. • The decrease of Ca²⁺ in vascular smooth muscle cells is related to Orai1 reduction. • ACE2/Ang-(1–7)/Mas axis is involved in IRW-induced E-cadherin upregulation. • IRW shows protective effects by reducing vascular remodeling, proliferation, and migration.