NFKB1 Gene Mutant Was Associated with Prognosis of Coronary Artery Disease and Exacerbated Endothelial Mitochondrial Fission and Dysfunction

Abstract

Endothelial apoptosis is the core pathological change in atherosclerotic cardiovascular disease, including coronary artery disease (CAD). Determining the molecular mechanisms underlying endothelial apoptosis is important. Nuclear factor kappa B (NF-κB) is a crucial transcription factor for controlling apoptosis. Our previous study demonstrated that the -94 ATTG ins/del mutant in the promoter of NFKB1 gene (rs28362491) is a risk factor for CAD. In the present study, we found that NFKB1 rs28362491 polymorphism was positively associated with increased major adverse cardiac and cerebrovascular events (MACCEs) in CAD patients. After adjusting for confounding factors including age, smoking, hypertension, glucose, and low-density lipoprotein cholesterol, the mutant DD genotype was an independent predictor of MACCEs ( OR = 2.578 , 95 % CI = 1.64 –4.05, P = 0.003 ). The in vitro study showed that mutant human umbilical vein endothelial cells (DD-mutant HUVECs) were more susceptible to high-glucose/palmitate-induced apoptosis, which was accompanied by decreased p50 expression and increased expression of cleaved caspase-3, Cytochrome c, and phospho-p65 ( P < 0.05 ). The mitochondrial membrane potential was significantly lower, while increasing levels of mtROS and more opening of the mPTP were observed in DD-mutant HUVECs ( P < 0.05 ). Furthermore, the percentage of cells with fragmented or spherical mitochondria was significantly higher in DD-mutant HUVECs than in wild-type cells (genotype II HUVECs) ( P < 0.05 ). In addition, after stimulation with high glucose/palmitate, the NFKB1 gene mutant significantly increased the expression of Drp1, which indicated that the NFKB1 gene mutant affected the expression of mitochondrial morphology-related proteins, leading to excessive mitochondrial fission. In conclusion, the mutant DD genotype of the NFKB1 gene was an independent predictor of worse long-term prognosis for CAD patients. DD-mutant HUVECs exhibited abnormal activation of the NF-κB pathway and increased Drp1 expression, which caused excessive mitochondrial fission and dysfunction, ultimately leading to increased apoptosis.

Frontiers and hotspots evolution in anti-inflammatory studies for coronary heart disease: A bibliometric analysis of 1990–2022

“…Similar results were shown according to the timeline of the research topic. The early 90s focused on traditional mechanisms such as tumor necrosis factor ( 97 , 98 ) and the mechanism of a nuclear transcription factor ( 99 – 101 ) in atherosclerosis. Several cytokines, including TNF-α, TGF-β, and different interleukins, are involved in developing various inflammatory cardiac pathologies ( 102 , 103 ).…”

Epigenome-Wide Changes in the Cell Layers of the Vein Wall When Exposing the Venous Endothelium to Oscillatory Shear Stress

“…Activation of cardiac IGF2R (insulin like growth factor 2 receptor) results in cardiomyocyte hypertrophy, cardiomyocyte proliferation, binucleation, or apoptosis [ 76 ]. NFKB1 (nuclear factor kappa B subunit 1) gene mutants affect the expression of mitochondrial morphology-related proteins, leading to excessive mitochondrial fission [ 77 ]. SOCS1 (suppressor of cytokine signaling 1) is a member of the STAT-induced STAT inhibitor.…”

Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases

“…This gene, linked to CAD, encodes for the nuclear factor kappa B (NF-κB) which has been demonstrated to induce, when mutated, increased sensitivity to oxidative stress-induced apoptosis in endothelial cells. NFKB1 gene mutation significantly increased the expression of DRP1 after stimulation with apoptotic stimuli, causing uncontrolled mitochondrial fission and mitochondrial dysfunction [ 114 ].…”