Mechanism of two alkaloids isolated from coral endophytic fungus for suppressing angiogenesis in atherosclerotic plaque in HUVEC

Atherosclerosis is a significant cause of many cardiovascular diseases. Oxidized low-density lipoproteins (ox-LDL) are crucial in developing atherosclerosis. In this study, we researched the effects of two alkaloids epi-aszonalenin A (EAA) and aszonalenin (AZN) of an endophytic fungus Aspergillus terreus C23-3 from coral Pavona, on ox-LDL-induced inflammation, apoptosis and angiogenesis in HUVEC, and evaluated related factors and mechanism. The results reveal that EAA and AZN inhibit HUVEC migration, invasion, angiogenesis and reactive oxygen species (ROS) accumulation on a non-cytotoxic basis. Then, EAA and AZN suppressed the ox-LDL-induced of LOX-1, VEGF protein expression, MAPK and PI3K/AKT pathways phosphorylation. Furthermore, AZN suppressed the ox-LDL-induced inflammatory factors (IL-6, IL-1β, and TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and VEGF receptor VEGFR-2 and platelet-derived growth factor PDGF. In addition, it inhibited ox-LDL-induced atherosclerosis by blocking inflammation and apoptosis through nuclear factor κB (NF-κB), cleaved-caspase-3 and Bax/Bcl-2 pathways. Molecular docking results confirm that the effect of AZN on atherosclerosis inhibitory activity may be attributed to hydrogen bonds formed into LOX-1 and VEGFR-2. These data indicate that EAA and AZN can effectively prevent ox-LDL-induced HUVEC damage and angiogenesis by inhibiting inflammation and apoptosis. Therefore, EAA and AZN may have potential beneficial effects in regulating atherosclerosis and plaque angiogenesis.