Abstract Background Atherosclerosis, a lipid-driven chronic inflammatory artery disease, is the main pathology underlying cardiovascular disease and remains the leading cause of death worldwide. Aging is a major risk factor, with cellular senescence (CS) contributing to disease progression. Senescent cells undergo metabolic reprogramming, but whether these changes contribute to the disease remains unclear. We hypothesize that CS drives metabolic imbalance in atherosclerosis. Methods Atherosclerosis was induced in 6-week-old wild-type mice by tail vein injection of AAV8-mPCSK9, followed by a high-cholesterol diet. Targeted metabolomics profiled the metabolic landscape of plaques at early and late disease stage vs. healthy aorta. In vitro, CS was induced in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) by 24h H2O2 exposure, followed by 7 days recovery. Cellular metabolism was analyzed using Seahorse. Results Mice receiving AAV8-mPCSK9 developed hyperlipidemia and atherosclerosis at early stage, with larger plaques in females at late-stage. Metabolomics revealed stage-specific dependent, but not sex-specific, metabolic profiles. Late-stage plaques were characterized by redox imbalance, decreased nucleotides and phosphocreatine, increased abundances of UDP-sugars and certain amino acids. In vitro, CS was confirmed in H2O2-treated ECs and VSMCs by an increase in SA-β-Gal, reduction in proliferation, and upregulation of p16, p21, and senescence-associated (SASP) genes. Senescent ECs showed elevated glycolytic capacity and reserve with modestly increased respiration. Senescent VSMCs showed only modest changes in glycolysis and respiration. Conclusion Our findings indicate that CS alters EC and VSMCs metabolism. Redox imbalance, energy depletion, and altered sugar and amino acid metabolism characterize advanced atherosclerosis and may be CS-driven. Ongoing studies will test whether senolytics reverse these alterations in vivo.
Steegen et al. (Fri,) studied this question.