NRP2 promotes atherosclerosis by upregulating PARP1 expression and enhancing low shear stress‐induced endothelial cell apoptosis

Abstract

Atherosclerosis-related cardiovascular diseases are leading causes of mortality worldwide, characterized by the development of endothelial cell dysfunction, increased oxidized low-density lipoprotein uptake by macrophages, and the ensuing formation of atherosclerotic plaque. Local blood flow patterns cause uneven atherosclerotic lesion distribution, and endothelial dysfunction caused by disturbed flow is an early step in the development of atherosclerosis. The present research aims to elucidate the mechanism underlying the regulation of Neuropilin 2 (NRP2) under low shear stress (LSS) in the atheroprone phenotype of endothelial cells. We observed that NRP2 expression was significantly upregulated in LSS-stimulated human umbilical vein endothelial cells (HUVECs) and in mouse aortic endothelial cells. Knockdown of NRP2 in HUVECs significantly ameliorated cell apoptosis induced by LSS. Conversely, overexpression of NRP2 had the opposite effect on HUVEC apoptosis. Animal experiments suggest that NRP2 knockdown markedly mitigated the development of atherosclerosis inApoe -/mice. Mechanistically, NRP2 knockdown and overexpression regulated PARP1 protein expression in the condition of LSS, which in turn affected the expression of apoptosis-related genes. Moreover, the upstream transcription factor GATA2 was found to regulate NRP2 expression in the progression of atherosclerosis. These findings suggest that NRP2 plays an essential proatherosclerotic role through the regulation of cell apoptosis, and the results reveal that NRP2 is a promising therapeutic target for the treatment of atherosclerotic disorders.

Proteome profiling of early gestational plasma reveals novel biomarkers of congenital heart disease

“…Among these, 80 proteins were significantly upregulated and 145 proteins were significantly downregulated (Student's t ‐test, P < 0.05, and fold change > 2 or < 0.5) in the CHD group (Fig 2D, Dataset EV5). These DEPs included several previously identified plasma CHD markers, such as neuropilin‐2, ATP‐citrate synthase (ACLY), protein S100‐A7 (S100A7), myosin regulatory light polypeptide 9 (MYL9), glucose‐6‐phosphate 1‐dehydrogenase (G6PD), serine hydroxymethyltransferase (SHMT1), coactosin‐like protein (COTL1), and plasminogen activator inhibitor 1 (SERPINE1) (Jain et al , 2004; Nembhard et al , 2017; Song et al , 2017; Ference et al , 2019; Xiong et al , 2019; Zhang et al , 2019; Tan et al , 2020; Luo et al , 2022). In addition, we identified other significantly changed proteins, such as deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) and secreted protein acidic and rich in cysteine (SPARC).…”

PARP-1 inhibitor alleviates liver lipid accumulation of atherosclerosis via modulating bile acid metabolism and gut microbes

“…Atherosclerosis, a chronic inflammatory and lipid-depository disease, has been regarded as the leading cause of morbidity and mortality in the Western world and is now the leading global cause of death. 20,21 PARP1, an important regulator in atherosclerosis, is involved in plaque formation, destabilization, monocyte differentiation, macrophage recruitment, 22,23 parthanatos of vascular smooth muscle cells, 24 endothelial dysfunction and apoptosis, 25,26 foam cell death, inflammatory responses, and disorders of lipid metabolism such as hyperlipidemia, alcoholic and non-alcoholic fatty liver disease, obesity, type II diabetes and its complications. 27,28 However, it is unknown how PARP1 inhibitors affect bile acid metabolism and gut microbiota and whether they can prevent atherosclerosis.…”

Identification of pathways and key genes in male late‑stage carotid atherosclerosis using bioinformatics analysis

“…Overproduction of ROS was reported to cause vascular endothelial damage ( 11 , 13 , 25 ). Endothelial dysfunction-induced lipid retention is an early feature of atherosclerotic lesion formation ( 26 ). Apoptosis of vascular smooth muscle cells is one of the major modulating factors of atherogenesis, which accelerates atherosclerosis progression by causing plaque destabilization and rupture ( 27 ).…”