As the primary pathological basis of atherosclerotic cardiovascular disease (ASCVD), atherosclerosis, is often life-threatening due to the lack of obvious symptoms at an early stage, and advancing age is a major risk factor for ASCVD. With ageing, immune cells such as monocytes, macrophages and neutrophils are largely affected as the haematopoietic stem cells (HSCs) lose regenerative capacity [
40]. Senescent cells accumulation is a major cause of age-related disease and might be driven by oxidative stress, DNA damage, telomere shortening and replicative exhaustion [
5]. Senescent foamy macrophages are considered to be deleterious at all stages of atherosclerosis, but the underlying mechanisms remain unclear. In this study, we excavated the SRGs in modulating the atherogenesis progression based on bioinformatics methods, and further functional investigation of hub DE-SRGs provide new insights into selective clearance of senescent cells-based atherosclerosis treatment.
Primarily, 15 DE-SRGs were screened based on two microarray datasets, and five hub DE-SRGs including ABI3, CAV1, NINJ1, Nox4 and YAP1 were identified via integrating three machine learning algorithms. The increased prevalence of NINJ1, a cell surface protein with two transmembrane domains, has been linked to many inflammatory diseases [
41]. Previous study have demonstrated that NINJ1 expression was enhanced in atherosclerotic aortas and colocalized with macrophages, and NINJ1 deficiency stimulated inflammatory response of macrophage through activating mitogen-activated protein kinase and blocking PI3K/Akt signaling pathway [
32]. Moreover, the expression of NINJ1 promoted p21 levels and G1 cell cycle arrest in Huh-7 hepatoma cells, and NINJ1-overexpressed cells showed increased SAβG activity, suggesting the vital role of NINJ1 in cellular senescence regulation [
42]. Studies have found that NADPH oxidases could act as the main source of ROS, and H
2O
2-producing NADPH oxidase Nox4 has anti-atherosclerotic functions via regulating compartmental redox states to co-ordinate varied signaling pathways [
34,
43,
44]. YAP protein was reported to adapt to atherosclerotic stimuli in a different regulatory manner. Macrophage YAP was up-regulated in human and mouse atherosclerotic plaque compared with non-atherosclerotic vessels, and YAP deficiency in macrophages mitigated atherosclerotic lesion formation [
45]. Of note, the levels of phosphorylated YAP (p-YAP) in the aorta of mice fed with a high-fat high-sucrose (HFHS) diet were increased at 2 weeks but decreased at 8 weeks [
33]. CAV1, a membrane protein essential for the formation of caveolae, regulates atherogenesis through alleviating transcytosis of low-density lipoprotein and inflammation response independent of increased NO production in endothelial cells. Interestingly, the expression of CAV1 is significantly attenuated in vascular smooth muscle cells in atherosclerotic lesions [
35], but highly expressed in the endothelium of atherosclerotic plaques, indicating its complex roles in atherogenesis. ABI3 has been identified as a critical regulator of WASp-family verprolin homologous protein 2 (WAVE2)-induced actin polymerization, which is necessary for cell motility in many functions including immune responses [
46]. Studies also have verified that ABI3 contributes to the pathogenesis of age-associated Alzheimer’s disease (AD) [
47,
48]. In this study, we established a predictive nomogram based on the five hub DE-SRGs, which displayed a good degree of discrimination and calibration, and could help distinguish the high-risk advanced atherosclerotic plaques in clinical.
Previous research has demonstrated that the ABI3 variant is associated with a range of cardiovascular traits, including hypertension, ischemic heart disease, and coronary atherosclerosis, based on phenome-wide association studies (PheWAS) [
49]. In our study, we have further explored the underlying mechanism of ABI3 in atherosclerosis progression. The results illustrated that the expression of ABI3 is significantly upregulated in macrophages of advanced plaques and senescent THP-1-derived macrophages. Furthermore, our findings suggest that the NF-κB signaling pathway plays a critical role in ABI3-mediated macrophage senescence. These findings provide new insights into the mechanism underlying atherosclerosis development and highlight the potential therapeutic utility of targeting the ABI3/NF-κB pathway for the prevention and treatment of this disease.