Angiogenic and Antiangiogenic mechanisms of high density lipoprotein from healthy subjects and coronary artery diseases patients

Abstract

Normal high-density lipoprotein (nHDL) in normal, healthy subjects is able to promote angiogenesis, but the mechanism remains incompletely understood. HDL from patients with coronary artery disease may undergo a variety of oxidative modifications, rendering it dysfunctional; whether the angiogenic effect is mitigated by such dysfunctional HDL (dHDL) is unknown. We hypothesized that dHDL compromises angiogenesis. The angiogenic effects of nHDL and dHDL were assessed using endothelial cell culture, endothelial sprouts from cardiac tissue from C57BL/6 mice, zebrafish model for vascular growth and a model of impaired vascular growth in hypercholesterolemic low-density lipoprotein receptor null(LDLr -/- )mice. MiRNA microarray and proteomic analyses were used to determine the mechanisms. Lipid hydroperoxides were greater in dHDL than in nHDL. While nHDL stimulated angiogenesis, dHDL attenuated these responses. Protein and miRNA profiles in endothelial cells differed between nHDL and dHDL treatments. Moreover, nHDL suppressed miR-24-3p expression to increase vinculin expression resulting in nitric oxide (NO) production, whereas dHDL delivered miR-24-3p to inhibit vinculin expression leading to superoxide anion (O 2 •- ) generation via scavenger receptor class B type 1. Vinculin was required for endothelial nitric oxide synthase (eNOS) expression and activation and modulated the PI3K/AKT/eNOS and ERK1/2 signaling pathways to regulate nHDL- and VEGF-induced angiogenesis. Vinculin overexpression or miR-24-3p inhibition reversed dHDL-impaired angiogenesis. The expressions of vinculin and eNOS and angiogenesis were decreased, but the expression of miR-24-3p and lipid hydroperoxides in HDL were increased in the ischemic lower limbs of hypercholesterolemic LDLr -/- mice. Overexpression of vinculin or miR-24-3p antagomir restored the impaired-angiogenesis in ischemic hypercholesterolemic LDLr -/- mice. Collectively, nHDL stimulated vinculin and eNOS expression to increase NO production by suppressing miR-24-3p to induce angiogenesis, whereas dHDL inhibited vinculin and eNOS expression to enhance O 2 •- generation by delivering miR-24-3p to impair angiogenesis, and that vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.

CircRtn4 Acts as the Sponge of miR-24-3p to Promote Neurite Growth by Regulating CHD5

“…In recent years, miR-24-3p has been reported to be involved in the pathogenesis of cardiovascular disease (Li et al, 2020;Qiao et al, 2020). More studies have focused on its roles FIGURE 6 | CircRtn4 promotes neurite growth via miR-24-3p.…”

“…In recent years, miR-24-3p has been reported to be involved in the pathogenesis of cardiovascular disease ( Li et al, 2020 ; Qiao et al, 2020 ). More studies have focused on its roles in cell apoptosis, proliferation, migration and invasion in various cancers, including glioma ( Xu et al, 2013 ), lung cancer ( Yan et al, 2018 ), bladder cancer ( Yu et al, 2017 ) and hepatocellular carcinoma ( Fan et al, 2018 ).…”

Screening and identification of NOTCH1, CDKN2A, and NOS3 as differentially expressed autophagy-related genes in erectile dysfunction

“…Therefore, NGFR may be involved in the regulation of endothelial autophagy. Hsa-mir-24-3p and Hsa-mir-335-5p, which control more ARGs, perform a key role in angiogenesis (Esquinas et al, 2017;Li et al, 2020). The relationship between AR, FLCN, and endothelial dysfunction requires further study.…”

Simvastatin inhibits POVPC-mediated induction of endothelial-to-mesenchymal cell transition

“…The relative change was analyzed using the ImageJ analysis software, as described previously ( 29 , 30 , 31 ). In addition, the supernatant from each well was used to detect the generation of NO using a Sievers NOA analyzer (GE Analytical Instruments, Boulder, CO) as described previously ( 32 , 33 ).…”