Exploring the Roles of CREBRF and TRIM2 in the Regulation of Angiogenesis by High-Density Lipoproteins

Abstract

Angiogenesis, the process of forming new blood vessels, is crucial in the physiological response to ischemia, though it can be detrimental as part of inflammation and tumorigenesis. We have previously shown that high-density lipoproteins (HDL) modulate angiogenesis in a context-specific manner via distinct classical signalling pathways, enhancing hypoxia-induced angiogenesis while suppressing inflammatory-driven angiogenesis. Whether additional novel targets exist to account for these effects are unknown. A microarray approach identified two novel genes, cyclic-adenosine-monophosphate-response-element-binding protein 3 regulatory factor (CREBRF) and tripartite motif-containing protein 2 (TRIM2) that were upregulated by reconstituted HDL (rHDL). We measured CREBRF and TRIM2 expression in human coronary artery endothelial cells following incubation with rHDL and exposure to either hypoxia or an inflammatory stimulus. We found that CREBRF and TRIM2 mRNA were significantly upregulated by rHDL, particularly in response to its phospholipid component 1-palmitoyl-2-linoleoyl-phosphatidylcholine, however, protein expression was not significantly altered. Knockdown of TRIM2 impaired endothelial cell tubulogenesis in vitro in both hypoxia and inflammation, implying a necessary role in angiogenesis. Furthermore, TRIM2 knockdown attenuated rHDL-induced tubule formation in hypoxia, suggesting that it is important in mediating the pro-angiogenic action of rHDL. Our study has implications for understanding the regulation of angiogenesis in both of these pathophysiological contexts by HDL.

Expression profile of Tripartite motif family (TRIM) in human fibroblasts (NHDF) infected with porcine endogenous retrovirus (PERV)

“… 41 TRIM2 differs from other members of TRIM family because it contains only one B‐box domain 42 . As in our study, TRIM2 overexpression in inflammatory cells was also observed by others researchers 43 . TRIM2 knock‐out mice and primary fibroblasts from patients with TRIM2 mutations are more susceptible to the infection with hemorrhagic fever due to New World arenavirus (NWA) 44 .…”

hsa_circ_0001947 Suppresses Acute Myeloid Leukemia Progression Via Targeting hsa-miR-329-5p / CREBRF axis

“…Furthermore, some studies verified CREBRF participate in the regulation of angiogenesis by high-density lipoproteins [40]. In addition, it had been reported that tumor suppressor in glioblastoma by blocking hypoxia-induced autophagy via the CREB3/ATG5 pathway [38].…”

A murine model of the human CREBRFR457Qobesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress

“…Thus far, the CREBRF R457Q variant is associated with increased obesity risk and decreased diabetes risk in humans (6,9,(11)(12)(13)(14) as well as height (8, 10) and body composition/lean mass (38). However, the endogenous wild-type (non-variant) CREBRF gene/protein has been linked, either directly or indirectly, to many other clinically-relevant physiological and/or pathological processes in mammals, including susceptibility to viral infection (29), endometrial function during pregnancy (31), angiogenesis (39), neuroendocrine function and behavior (17), Alzheimer's disease (40), and cancer (32,(41)(42)(43)(44)(45). Thus, there continues to be an urgent need to understand the mechanism by which this gene/protein contributes to normal biology and disease, and in particular, the specific effect of the CREBRF R457Q variant, which is highly prevalent in Oceanic populations.…”