Apolipoprotein A-I Mimetic Peptide Restores VEGF-induced Angiogenesis in Hypercholesterolemic Ischemic Heart by Reducing HDL Proinflammatory Properties

VEGF-induced angiogenesis is impaired in hypercholesterolemia. Previous studies showed that an apolipoprotein A-I(ApoA-I) mimetic peptide, D-4F, is able to reduce HDL proinflammatory index in hypercholesterolemia. Whether D-4F promotes angiogenesis in hypercholesterolemia remains unclear. Low-density lipoprotein receptor null (LDLr-/-) mice and LDLr-/-/ApoA-I-/- mice were fed with high-fat diet with or without D-4F (1mg/kg<middle dot>d). C57BL/6 mice fed with normal diet served as control. The myocardial infarction was induced by ligation coronary artery, and the VEGFA-AAV 9 was injected in heart. The plasma HDL proinflammatory index, cardiac function, infarct size, and angiogenesis related signaling pathways were examined. The HDL proinflammatory index increases in hypercholesterolemic mice. VEGFA stimulates angiogenesis and improves cardiac function in ischemic heart of C57BL/6 mice, but not in hypercholesterolemic mice. D-4F reduces HDL proinflammatory index. D-4F combined with VEGFA stimulates the expression of CD31 and eNOS, activates ERK1/2, reduces infarct size, and improves cardiac function in ischemic heart in hypercholesterolemic LDLr-/- mice but not in hypercholesterolemic LDLr-/-/ApoA-I-/- mice. D-4F restores the VEGF-induced angiogenesis by reducing HDL proinflammatory properties in hypercholesterolemic ischemic heart.Graphical abstractIn the presence of ApoA-I, D-4F promotes angiogenesis by restoring the anti-inflammatory properties of HDL to improve HDL function. Solid arrow:direct effect, Dotted arrow:indirect effect, Grey word:mechanisms described in previous literature