Abstract
Among autophagy-related molecules, p62/SQSTM1 is an adaptor for identifying and delivering intracellular cargo for degradation. Since ubiquitination is reversible, it has a switch role in autophagy. Ubiquitination is also involved in regulating autophagy in a timely manner. This study aimed to elucidate how p62-mediated autophagy is regulated in human endothelial cells and macrophages under atherosclerotic conditions, focusing on the lysosomal and proteasomal pathways. Co-cultured HUVECs and THP-1 cells were exposed to oxLDL (50 μg/mL) and autophagy was assessed. To downregulate p62, siRNA was administered, and the E3 ligases were inhibited by Heclin or MLN4924 treatment under the condition that cellular inflammatory processes were stimulated by oxLDL simultaneously initiated autophagy. Downregulating p62 induced an alternative degradation system, and the E3 ligases were found to be involved in the progression of atherosclerosis. Collectively, the present study demonstrated that the endothelial lipid accumulation under atherosclerotic conditions was caused by lysosomal dysfunction associated with autophagy.
Highlights
Endothelial dysfunction, as a pathological condition, is considered a crucial event in the progression of atherosclerosis
C1q regulates chemokine production from macrophages during atherosclerosis, so we primarily evaluated its levels in our cell culture model
The protein levels of C1q were increased in co-cultured human umbilical vein endothelial cells (HUVEC), which triggered inflammation in the THP-1 cells, as determined by detectable cleaved IL-1β protein levels (Figure 1)
Summary
Endothelial dysfunction, as a pathological condition, is considered a crucial event in the progression of atherosclerosis. Accumulated lipid in the arterial walls is one of the definitive features of atherosclerosis, and endothelial cell dysfunction in the inner wall of the vessel is an early event in atherosclerotic plaque formation [4,5]. Autophagy is one of the responses to toxic intermediates found in atherosclerotic plaques, and autophagic processes concomitantly increase in macrophages [8]. Autophagy serves as a safeguard, for cells with atherosclerotic plaques, against cellular oxidative stress by polarizing mitochondria and preventing cytochrome c release [9]. Autophagy deficiency in macrophages increases their susceptibility to foam cell formation, which plays an essential role in the atherosclerotic process. Given the stabilizing nature of plaques on rupture-prone lesions, the induction of autophagy in macrophages might be a promising strategy in plaques that are not obstructing the lumen, but are prone to rupture [11]
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