Abstract
Autophagy is an important process in the pathogenesis of atherosclerosis. C1q/tumor necrosis factor-related protein 9 (CTRP9) is the closest adiponectin paralog. CTRP9 has anti-aging and anti-atherogenic effects, but its roles in autophagy and endothelial senescence are currently unknown. This study aimed to evaluate whether CTRP9 prevents palmitic acid (PA)-induced endothelial senescence by promoting autophagy. After no treatment or pre-treatment of human umbilical vein endothelial cells with CTRP9 prior to PA treatment, the level of senescence was measured by senescence associated acidic β-galactosidase staining and the level of hyperphosphorylated pRB protein. Autophagy was evaluated by LC3 conversion and the level of p62/SQSTM1, a protein degraded during autophagy. Autophagosome–lysosome fusion was detected by fluorescence microscopy. Pre-treatment with CTRP9 attenuated PA-induced endothelial senescence. CTRP9 increased the conversion of LC3-I to LC3-II and decreased p62 levels in a time- and dose-dependent manner. Although both CTRP9 and PA treatment increased LC3 conversion, treatment with PA increased the expression level of p62 and decreased the fusion of autophagosomes and lysosomes, which represented decreased autophagic flux. However, pre-treatment with CTRP9 recovered the autophagic flux inhibited by PA. AMP-activated kinase (AMPK) activation was involved in LC3 conversion and decreased p62 levels induced by CTRP9. CTRP9 inhibits PA-induced endothelial senescence by recovering autophagy and autophagic flux through AMPK activation.
Highlights
Autophagy is an important process in the pathogenesis of atherosclerosis
human umbilical vein endothelial cells (HUVEC) were treated with 500 μM of palmitic acid (PA) for 24 hours to examine the effects of PA on endothelial senescence
When HUVECs were pre-treated with 3 μg/mL of C1q/tumor necrosis factor-related protein 9 (CTRP9) for 1 hour before PA treatment, the number of SA-β-Gal-positive cells was significantly decreased compared to the cells treated with PA alone (Fig. 1A, right lower)
Summary
Autophagy is an important process in the pathogenesis of atherosclerosis. C1q/tumor necrosis factor-related protein 9 (CTRP9) is the closest adiponectin paralog. The aim of this study was to evaluate whether CTRP9 prevents palmitic acid (PA)-induced endothelial senescence by promoting autophagy. Aging of endothelial cells is an independent risk factor of atherosclerosis-related diseases such as myocardial infarction, ischemic heart diseases, and stroke [1]. Both aging and atherosclerosis are significantly associated with endothelial cellular senescence. Exposure to high concentrations of palmitic acid (PA), the most abundant saturated FFA in human plasma, promotes endothelial dysfunction and inhibits endothelium repair through the increase in inhibitor of nuclear factor-kappa-B kinase subunit beta (IKKβ) activity [7], which is the main signaling pathway responsible for cellular senescence [8]
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