MTR4 deficiency attenuates abdominal aortic aneurysm progression through suppressing VSMC senescence via the MTR4-RAP1a axis

Abstract

Summary Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by progressive aortic dilation, with insidious onset but high mortality after rupture and limited treatment options. Vascular smooth muscle cell (VSMC) senescence is a key driver of AAA progression. RNA helicase MTR4 has been reported to function in cardiovascular disorders, laying a foundation for exploring its aortic pathological functions. Our research findings indicate that MTR4 was significantly upregulated in both human and murine AAA tissues. Mendelian randomization indicated a suggestive causal association between elevated MTR4 expression and increased AAA risk. In vivo, MTR4 deficiency markedly attenuated VSMC senescence and suppressed AAA formation in mice. Functional studies confirmed that MTR4 promotes VSMC senescence and AAA progression by activating the Rap1 pathway through regulation of RAP1a and its activator RASGRP2. RAP1a silencing abrogated MTR4-driven VSMC senescence. This work identifies MTR4 as a potential therapeutic target for AAA.