DOI: 10.1161/circ.148.suppl_1.16495 ISSN: 0009-7322

Abstract 16495: Cellular Senescence and Mitochondrial Dysfunction in Very Low-Density Lipoprotein-Induced Cardio-Lipotoxicity

Yi-Hsiung Lin, Hsiang-chun Lee
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Dyslipidemia, the hallmark of the metabolic syndrome, plays an important role in cardiovascular and cardiometabolic diseases. The heart utilizes lipids as major source of ATP and cardiomyocytes expresses abundant receptors for very low-density lipoprotein (VLDL), which is found exhibiting cardio-lipotoxicity in the metabolic syndrome. This study investigates the effects of VLDL in cardiomyocyte senescence and mitochondrial function. VLDL from metabolic syndrome patients was used to treat H9C2 cardiomyocytes for 72 hours. The RNA-sequencing was conducted to find novel senescence-associated signaling pathways in VLDL-induced lipotoxicity. The newly-found targets and regulators were validated using qPCR and Western blot. In addition, the senescence-associated secretory phenotype, the effects of VLDL on mitochondrial ATP production, NAD + /NADH, and mitochondrial membrane potential were also determined. The results showed that VLDL upregulated 97 cardiac hypertrophy-related genes expression. Among them, 84 genes were related to senescence, and 30 genes were apoptosis-related. Besides, 63 autophagy genes were also affected by VLDL treatment. The KEGG analysis showed that VLDL induced multiple senescence-related signaling pathways such as TP53, ERK-FOXO4, and TGF-β-related pathway. VLDL also exhibited dose-dependent influence on intra-mitochondrial Ca 2+ , and associated molecule Hmox1, Htt and Xdh expression. This study revealed novel mechanisms for the VLDL-induced cardio-lipotoxicity, which was shown involving multiple senescence-related signaling pathways and mitochondrial function regulators. The results suggested that the senescence signaling is a potential therapeutic target for cardiometabolic diseases.

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