Defective autophagy in vascular smooth muscle cells promote uremic accelerated atherosclerosis.

Individuals with chronic kidney disease (CKD) exhibit a significantly elevated risk of premature mortality, predominantly attributable to cardiovascular etiologies. Atherosclerosis is a multifactorial vascular pathology driven by dysregulated lipid metabolism. Notably, patients with CKD exhibit an accelerated progression of atherosclerosis, a condition referred to as uremia-accelerated atherosclerosis (UAAS). Autophagy represents an evolutionarily conserved cellular process that plays a pivotal role in maintaining intracellular homeostasis across cardiovascular cell types. However, the involvement of autophagy in UAAS remains unclear. This study aimed to determine the underlying mechanisms of autophagy in the regulation of UAAS. Autophagy-related differentially expressed genes in UAAS were identified by bioinformatic analysis of GSE135626 dataset. Enrichment analysis showed that autophagy-related DEGs were significantly enriched in regulation of autophagy and PI3K/PKB pathway. Western blotting was used to detect the protein expression levels of Beclin 1, P62, and LCII, and phosphorylation of PI3K and PKB. The result showed that the autophagy level and the phosphorylation levels of PI3K and PKB were decreased in the UAAS group. In vitro, uremic serum induced vascular smooth muscle cells (VSMCs) autophagy dysfunction and reduced phosphorylation of PI3K and PKB. Then 10 hub genes were identified by protein-protein interaction (PPI) network analysis and qRT-PCR confirmed that the expression of Atg5, Atg3, Petn and HIF-1α were down-regulated in VSMCs exposure to uremic serum. These data demonstrate that defective autophagy in atherosclerotic lesions and VSMCs by down-regulating PI3K/PKB pathway exacerbates atherosclerosis progression and promotes cellular damage. These findings elucidate potential molecular mechanisms underlying UAAS pathogenesis and suggest novel therapeutic avenues for clinical intervention.