医学
还原(数学)
腹主动脉瘤
表型
心脏病学
内科学
主动脉瘤
动脉瘤
平滑肌
放射科
基因
遗传学
几何学
数学
生物
作者
Jack Bontekoe,Ting Zhou,Huan Yang,Michelle Conte,Zulmari Silva-Pedraza,Courtney E. Morgan,David D. Aufhauser,Paul D. DiMusto,Bo Liu
标识
DOI:10.1016/j.jvs.2024.03.411
摘要
Vascular smooth muscle cell (SMC) loss and phenotype switch promote abdominal aortic aneurysm (AAA) development, yet whether strategically enhancing positive aortic wall remodeling can reduce AAA rupture is unknown. We hypothesize inhibiting necroptosis signaling in SMCs may drive differentiation into resilient and regenerative phenotypes, thus reinforcing AAA wall integrity and rupture resistance. We developed Cre-loxP transgenic mice with SMC-specific loss-of-function mutation of the necroptosis regulatory gene, Ripk3 (Ripk3Δ). AAAs were induced using the topical elastase plus β-aminopropionitrile murine model. Human aortic samples were collected during elective and ruptured AAA repair, aortic reconstruction, and solid organ transplantation. Rupture-free survival at 56-days post-AAA induction was drastically improved with both homozygous and heterozygous loss of SMC RIPK3 function (Ripk3ΔHO: 100%, Ripk3ΔHet: 92.3% vs Ripk3ΔWT: 47.1%). Ripk3 mutant aortas demonstrated rupture- resistance despite substantial aneurysmal dilations ranging from 127% to 527%, and morphologically displayed significant medial thickening with SMC expansion. Bulk RNA-sequencing revealed stark transcriptional changes between 14-day Ripk3ΔHO and Ripk3ΔWT aortas. Both genotypes showed typical aneurysmal processes; however, Ripk3 depletion greatly reduced aneurysm-induced inflammatory responses. We identified 54 uniquely altered transcripts in mutant tissues, coding for cell cycle regulators and extracellular matrix proteins. Ongoing tissue analysis will determine whether regenerative, matrix-producing SMCs vary among human AAAs and healthy aortas. AAA rupture is significantly reduced by inhibiting RIPK3 in SMCs, likely by promoting positive structural adaptations and down-regulating classic pathways of aneurysmal degeneration. We postulate pharmacologically inhibiting RIPK3-mediated SMC modulation could be a novel approach in AAA patient management, to reduce rupture risk from diagnosis to optimal timing of surgical repair.Fig 2Representative images of 56-day gross aortas (above) and H&E histology (below) displaying increased media thickness and cellularity in mutant AAA tissues.View Large Image Figure ViewerDownload Hi-res image Download (PPT)
科研通智能强力驱动
Strongly Powered by AbleSci AI