Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

TM6SF2 reduces lipid accumulation in vascular smooth muscle cells by inhibiting LOX-1 and CD36 expression.

TM6SF2, predominantly expressed in the liver and intestine, is closely associated with lipid metabolism. We have demonstrated the presence of TM6SF2 in VSMCs within human atherosclerotic plaques. Subsequent functional studies were conducted to investigate its role in lipid uptake and accumulation in human vascular smooth muscle cells (HAVSMCs) using siRNA knockdown and overexpression techniques. Our results showed that TM6SF2 reduced lipid accumulation in oxLDL-stimulated VSMCs, likely through the regulation of lectin-like oxLDL receptor 1 (LOX-1) and scavenger receptor cluster of differentiation 36 (CD36) expression. We concluded that TM6SF2 plays a role in HAVSMC lipid metabolism with opposing effects on cellular lipid droplet content by downregulation of LOX-1 and CD36 expression.

Effect of spermidine on ameliorating spermatogenic disorders in diabetic mice via regulating glycolysis pathway.

Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM's effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM's protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What's more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP's positive effect on moderating spermatogenic disorder in T1DM mice's testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway's activation.

Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress.

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-ß-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

Effect of PCSK9 on Vascular Smooth Muscle Cell Functions: A New Player in Atherosclerosis.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the "pleiotropic" effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.

Hydrogen sulfide improves ox­LDL­induced expression levels of Lp­PLA2 in THP­1 monocytes via the p38MAPK pathway.

Hydrogen sulfide (H2S) exerts an anti­atherosclerotic effect and decreases foam cell formation. Lipoprotein­associated phospholipase A2 (Lp­PLA2) is a key factor involved in foam cell formation. However, the association between H2S and Lp­PLA2 expression levels with respect to foam cell formation has not yet been elucidated. The present study investigated whether H2S can affect foam cell formation and potential signalling pathways via regulation of the expression and activity of Lp­PLA2. Using human monocytic THP­1 cells as a model system, it was observed that oxidized low­density lipoprotein (ox­LDL) not only upregulates the expression level and activity of Lp­PLA2, it also downregulates the expression level and activity of Cystathionine γ lyase. Exogenous supplementation of H2S decreased the expression and activity of Lp­PLA2 induced by ox­LDL. Moreover, ox­LDL induced the expression level and activity of Lp­PLA2 via activation of the p38MAPK signalling pathway. H2S blocked the expression levels and activity of Lp­PLA2 induced by ox­LDL via inhibition of the p38MAPK signalling pathway. Furthermore, H2S inhibited Lp­PLA2 activity by blocking the p38MAPK signaling pathway and significantly decreased lipid accumulation in ox­LDL­induced macrophages, as detected by Oil Red O staining. The results of the present study indicated that H2S inhibited ox­LDL­induced Lp­PLA2 expression levels and activity by blocking the p38MAPK signalling pathway, thereby improving foam cell formation. These findings may provide novel insights into the role of H2S intervention in the progression of atherosclerosis.

Effects of gut microbiota on atherosclerosis through hydrogen sulfide.

Cardiovascular diseases are the leading cause of death and morbidity worldwide. Atherosclerotic cardiovascular disease (ASCVD) is affected by both environmental and genetic factors. Microenvironmental disorders of the human gut flora are associated with a variety of health problems, not only gastrointestinal diseases, such as inflammatory bowel disease, but also extralintestinal organs. Hydrogen sulfide (H2S) is the third gas signaling molecule other than nitric oxide and carbon monoxide. In the cardiovascular system, H2S plays important roles in the regulation of blood pressure, angiogenesis, smooth muscle cell proliferation and apoptosis, anti-oxidative stress, cardiac functions. This review is aiming to explore the potential role of gut microbiota in the development of atherosclerosis through hydrogen sulfide production as a novel therapeutic direction for atherosclerosis.

The Role of Ubiquitin E3 Ligase in Atherosclerosis.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

Role of oral microbiota in atherosclerosis.

Oral infections are common among individuals of all ages and can activate local and systemic inflammation. The inflammatory response plays an important role in atherosclerosis. An increasing number of studies have reported an association between oral pathogen infection and atherosclerotic coronary heart disease. For instance, epidemiological studies support the positive correlation between oral infections and atherosclerosis. The presence of oral pathogens in human atherosclerotic plaques has been detected by multiple methods, and oral infections promote atherosclerosis in animal experiments. Various mechanisms are involved in oral infections, thereby promoting atherosclerosis. First, oral infections can trigger the local and systemic inflammatory response, causing vascular endothelial damage. Oral-derived pathogens that enter atherosclerotic plaque can activate macrophages and cause an intra-plaque inflammatory response. Second, oral infections can promote intra-plaque macrophage cholesterol accumulation and foam cell formation. Third, oral infections can regulate plasma lipid levels, thereby increasing atherogenic lipid low-density lipoprotein and triglyceride levels. Although atherosclerosis caused by oral infections is currently studied, the precise mechanism remains to be further explored. The rise of gut microbiota research also makes the relationship between oral microbiota and disease, especially the relationship with coronary heart disease, worthy of attention and in-depth research.

Macrophage polarization in atherosclerosis.

Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.

Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation.

Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (Pmax), minimum P-wave duration (Pmin), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RT-PCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging Pmax, Pmin, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect.

PCSK9: A new participant in lipophagy in regulating atherosclerosis?

Proprotein convertase subtilisin kexin 9 (PCSK9) regulates lipid metabolism by degrading low-density lipoprotein receptor on the surface of hepatocytes. PCSK9-mediated lipid degradation is associated with lipophagy. Lipophagy is a process by which autophagosomes selectively sequester lipid-droplet-stored lipids and are delivered to lysosomes for degradation. Lipophagy was first discovered in hepatocytes, and its occurrence provides important fundamental insights into how lipid metabolism regulates cellular physiology and pathophysiology. Furthermore, PCSK9 may regulate lipid levels by affecting lipophagy. This review will discuss recent advances by which PCSK9 mediates lipid degradation via the lipophagy pathway and present lipophagy as a potential therapeutic target for atherosclerosis.

Hydrogen sulfide inhibits PCSK9 expression through the PI3K/Akt­SREBP­2 signaling pathway to influence lipid metabolism in HepG2 cells.

Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H2S regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of low­density lipoprotein receptor (LDLR) in a time­ and dose­dependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1'­dioctadecyl­3,3,3',3'­tetramethyl­indocarbocyanine perchlorate­labeled LDL (DiI­LDL) uptake in the H2S­treated HepG2 cells. Furthermore, the phosphoinositide 3­kinase (PI3K)/protein kinase B (Akt)­sterol regulatory element binding proteins 2 (SREBP­2) signaling pathway was confirmed to be involved in H2S­regulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiI­LDL for 24 h, and the results revealed that H2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/Akt­SREBP­2 signaling pathway. To the very best of our knowledge, this study is the first to report that H2S can regulate the expression of PCSK9.

Potential protective effects of red yeast rice in endothelial function against atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is the deadliest disease in the world, with endothelial injury occurring throughout the course of the disease. Therefore, improvement in endothelial function is of essential importance in the prevention of ASCVD. Red yeast rice (RYR), a healthy traditional Chinese food, has a lipid modulation function and also plays a vital role in the improvement of endothelial reactivity and cardiovascular protection; thus, it is significant in the prevention and treatment of ASCVD. This article reviews the molecular mechanisms of RYR and its related products in the improvement of endothelial function in terms of endothelial reactivity, anti-apoptosis of endothelial progenitor cells, oxidative stress alleviation and anti-inflammation.

Tissue factor pathway inhibitor in atherosclerosis.

Tissue factor pathway inhibitor (TFPI) reduces the development of atherosclerosis by regulating tissue factor (TF) mediated coagulation pathway. In this review, we focus on recent findings on the inhibitory effects of TFPI on endothelial cell activation, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory cell recruitment and extracellular matrix which are associated with the development of atherosclerosis. Meanwhile, we are also concerned about the impact of TFPI levels and genetic polymorphisms on clinical atherogenesis. This article aims to explain the mechanism in inhibiting the development of atherosclerosis and clinical effects of TFPI, and provide new ideas for the clinical researches and mechanism studies of atherothrombosis.

Fibroblast growth factor-21 alleviates hypoxia/reoxygenation injury in H9c2 cardiomyocytes by promoting autophagic flux.

Fibroblast growth factor (FGF)­21, a member of the family of FGFs, exhibits protective effects against myocardial ischemia and ischemia/reperfusion injury; it is also an enhancer of autophagy. However, the mechanisms underlying the protective role of FGF­21 against cardiomyocyte hypoxia/reoxygenation (H/R) injury remain unclear. The present study aimed to investigate the effect of FGF­21 on H9c2 cardiomyocyte injury induced by H/R and the mechanism associated with changes in autophagy. Cultured H9c2 cardiomyocytes subjected to hypoxia were treated with a vehicle or FGF­21 during reoxygenation. The viability of H9c2 rat cardiomyocytes was measured using Cell Counting Kit­8 and trypan blue exclusion assays. The contents of creatine kinase (CK) and creatine kinase isoenzymes (CK­MB), cardiac troponin I (cTnT), cardiac troponin T (cTnI) and lactate dehydrogenase (LDH) in culture medium were detected with a CK, CK­MB, cTnT, cTnI and LDH assay kits. The protein levels were examined by western blot analysis. Autophagic flux was detected by Ad­mCherry­GFP­LC3B autophagy fluorescent adenovirus reagent. The results indicated that FGF­21 alleviated H/R­induced H9c2 myocardial cell injury and enhanced autophagic flux during H/R, and that this effect was antagonized by co­treatment with 3­methyladenine, an autophagy inhibitor. Furthermore, FGF­21 increased the expression levels of Beclin­1 and Vps34 proteins, but not of mechanistic target of rapamycin. These data indicate that FGF­21 treatment limited H/R injury in H9c2 cardiomyocytes by promoting autophagic flux through upregulation of the expression levels of Beclin­1 and Vps34 proteins.

PCSK9: A novel inflammation modulator in atherosclerosis?

Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the secretory serine protease family. It binds to low-density lipoprotein receptor (LDLR) for endocytosis and lysosome degradation in the liver, resulting in an increasing in circulating LDL-cholesterol (LDL-c) level. Since a PCSK9 induced increase in plasma LDL-c contributes to atherosclerosis, PCSK9 inhibition has become a new strategy in preventing and treating atherosclerosis. However, in addition to the effect of PCSK9 on elevating blood LDL-c levels, accumulating evidence shows that PCSK9 plays an important role in inflammation, likely representing another major mechanism for PCSK9 to promote atherosclerosis. In this review, we discuss the association of PCSK9 and inflammation, and highlight the specific effects of PCSK9 on different vascular cellular components involved in the atherosclerotic inflammation. We also discuss the clinical evidence for the association between PCSK9 and inflammation in atherosclerotic cardiovascular disease. A better understanding of the direct association of PCSK9 with atherosclerotic inflammation might help establish a new role for PCSK9 in vascular biology and identify a novel molecular mechanism for PCSK9 therapy.

Role of PCSK9 in lipid metabolism and atherosclerosis.

Elevated plasma low-density lipoprotein cholesterol (LDL-C) is an important risk factor for cardiovascular diseases. Statins are the most widely used therapy for patients with hyperlipidemia. However, a significant residual cardiovascular risk remains in some patients even after maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new pharmacologically therapeutic target for decreasing LDL-C. PCSK9 reduces LDL intake from circulation by enhancing LDLR degradation and preventing LDLR recirculation to the cell surface. Moreover, PCSK9 inhibitors have been approved for patients with either familial hypercholesterolemia or atherosclerotic cardiovascular disease, who require additional reduction of LDL-C. In addition, PCSK9 inhibition combined with statins has been used as a new approach to help reduce LDL-C levels in patients with either statin intolerance or unattainable LDL goal. This review will discuss the emerging anti-PCSK9 therapies in the regulation of cholesterol metabolism and atherosclerosis.

PCSK9: A potential regulator of apoE/apoER2 against inflammation in atherosclerosis?

Atherosclerosis is characterized by chronic inflammation and lipid accumulation in arterial walls, resulting in several vascular events. Proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease, has a pivotal role in the degradation of hepatic low-density lipoprotein receptor (LDLR). It can increase plasma concentrations of low-density lipoprotein cholesterol and affect lipid metabolism. Recently, PCSK9 has been found to accelerate atherosclerosis via mechanisms apart from that involving the degradation of LDLR, with an emerging role in regulating the inflammatory response in atherosclerosis. Apolipoprotein E receptor 2 (apoER2), one of the LDLR family members expressed in macrophages, can bind to its ligand apolipoprotein E (apoE), exhibiting an anti-inflammatory role in atherosclerosis. Evidence suggests that apoER2 is a target of PCSK9. This review aims to discuss PCSK9 as a potential regulator of apoE/apoER2 against inflammation in atherosclerosis.