FEBS J. 2025 Nov 28. doi: 10.1111/febs.70341. Online ahead of print.
ABSTRACT
ACT-132577 is a newly approved anti-hypertensive agent in the treatment of hypertension and related cardiovascular diseases. However, its exact roles and underlying mechanisms beyond simple blood pressure regulation remain largely unclear. This study aims to elucidate the role of ACT-132577 in CTR1-copper-cuproptosis signalling and vascular injury. Twelve-week-old spontaneously hypertensive rats (SHRs) and eight-week-old C57BL/6J mice undergoing abdominal aortic constriction (AAC) and primary vascular smooth muscle cells (VSMCs) were used to investigate the effects of ACT-132577 on vascular remodelling. Administration of ACT-132577 effectively reduced copper levels and Copper Transporter 1 (CTR1) protein expression in aortic tissues. These changes were linked to alleviation of cuproptosis, evidenced by increased levels of Ferredoxin1, lipoylated-Dihydrolipoamide S-Acetyltransferase (lipo-DLAT) and lipo-Dihydrolipoamide S-Succinyltransferase (lipo-DLST), as well as lower levels of DLAT oligomer and heat shock protein 70. Additionally, both ACT-132577 and tetrathiomolybdate treatment strikingly mitigated vascular remodelling in SHRs, with decreases in medial thickness, vascular diameter and the cross-sectional area of blood vessels. In vitro experiments corroborated these findings, revealing that ACT-132577 suppressed platelet-derived growth factor subunit beta-induced VSMC phenotypic transition, which was evidenced by reduced cellular migration, maintained cell contractility, upregulated contractile markers (SM22a, Acta2, Myh11) and downregulated secretory markers (MMP2, MMP9, OPN). Mechanistically, ACT-132577 upregulated E3 ubiquitin-protein ligase NEDD4-like (NEDD4L), thus promoting K48 ubiquitination of CTR1. More importantly, knocking down NEDD4L significantly abolished the effects of ACT-132577 on cuproptosis and VSMC phenotypic transition. In conclusion, ACT-132577 plays a crucial role in cuproptosis and aortic remodelling by modulation of the NEDD4L-CTR1-copper signaling, providing a novel perspective on its therapeutic potential in mitigating pressure overload-induced vascular remodelling.
PMID:41313680 | DOI:10.1111/febs.70341