REDD1 Silencing Aggravates Aortic Dissection and Promotes VSMC Apoptosis with Autophagy-Related Changes

Background: Aortic dissection (AD) is a life-threatening vascular disease with high mortality, yet its molecular pathogenesis remains incompletely understood. This study investigated the role of regulated in development and DNA damage responses 1 (REDD1) in vascular smooth muscle cells (VSMCs) apoptosis and the underlying mechanisms. Methods: Single-cell RNA sequencing data from GSE222318 were analyzed to investigate the expression levels of REDD1 in VSMCs and its role in inducing apoptosis and autophagy. The target gene was silenced in C57BL/6J mice via tail-vein injection of Adeno-associated virus.β-aminopropionitrile (BAPN) was used for AD induction. Western blotting was used to assess REDD1, LC3B, p62, BAX, BCL-2 in aortic tissues. Aortic histopathological alterations were examined by hematoxylin and eosin (H&E), Elastica van Gieson (EVG), and Masson's trichrome staining. Immunofluorescence was performed to examine REDD1 expression and its localization in α-SMA-positive vascular smooth muscle cells. REDD1, LC3B, p62, BAX, BCL-2, mTOR, and p-mTOR were also examined by Western blotting in cultured cells. Mitochondrial membrane potential was evaluated by JC-1 staining, and apoptosis was assessed by flow cytometry. Results: REDD1 expression levels were significantly increased in human AD tissues and localized predominantly to medial VSMCs. REDD1 levels were positively correlated with BAX and LC3B and negatively correlated with BCL-2 and p62. Knockdown of REDD1 in AD mice was associated with increased levels of BAX and p62 and decreased levels of BCL-2 and LC3B in aortic tissues, accompanied by more severe pathological manifestations. REDD1 silencing in VSMCs increased BAX, p62 and p-mTOR while reducing BCL-2 and LC3B, accompanied by increased apoptosis and loss of mitochondrial membrane potential, whereas rapamycin reduced apoptosis and alleviated mitochondrial injury. Conclusions: REDD1 appears to play a protective, compensatory role in AD. Increased REDD1 expression may help preserve mitochondrial membrane potential and attenuate VSMC apoptosis under pathological stress, accompanied by changes in static autophagy-related markers that suggest a possible association with increased autophagic activity. Loss of REDD1 activity promotes mitochondrial injury and VSMC apoptosis, thereby aggravating AD. Targeting REDD1 may therefore represent a potential therapeutic strategy for AD.