Introduction
Atherosclerosis (AS) is the principal pathological
basis of cardiovascular and cerebrovascular diseases, and is
fundamentally a chronic inflammatory disorder. In particular,
coronary artery disease remains a leading cause of mortality
worldwide (1), accounting for ~1 in
4 mortalities, and is responsible for an estimated 17.8 million
mortalities annually (1).
The development of AS typically is initiated by
endothelial activation, followed by monocyte adhesion to the
activated endothelium, transendothelial migration and subsequent
differentiation into macrophages (2). Macrophages play a key role in the
progression of AS. From a pathological perspective,
macrophage-derived foam-cell formation follows a well-defined
sequence of events. During early AS, endothelial activation and
dysfunction facilitate the subendothelial retention and
modification of apolipoprotein B-containing lipoproteins,
particularly low-density lipoprotein (LDL). Oxidized (ox)-LDL and
other modified lipoproteins then promote the recruitment of
circulating monocytes, which adhere to the activated endothelium,
migrate into the intima and differentiate into macrophages. These
macrophages take up large quantities of ox-LDL predominantly
through scavenger receptors such as class A scavenger receptor
(SR-A) and CD36, leading to progressive accumulation of cholesteryl
ester in cytoplasmic lipid droplets and the generation of
lipid-laden foam cells. Clusters of foam cells give rise to fatty
streaks, the earliest detectable atherosclerotic lesions, which can
subsequently develop into advanced plaques containing a necrotic
core and thin fibrous cap in the setting of persistent lipid
overload, chronic inflammatory activation and defective
efferocytosis (2-4).
From the initial lesion formation to the progression toward
vulnerable plaques, accumulating evidence suggests that modulation
of macrophage polarization can effectively influence disease
progression (3). Macrophages
internalize substantial levels of ox-LDL through the scavenger
receptor SR-A, thereby promoting their transformation into
lipid-laden foam cells, while the cholesterol transporter
ATP-binding cassette subfamily G member 1 (ABCG1) mediates
cholesterol efflux (4,5). Thus, maintenance of the balance
between cholesterol influx and efflux is crucial for the
development of targeted therapeutic strategies for AS.
Monoclonal antibodies directed against proprotein
convertase subtilisin/kexin type 9 (PCSK9) have become an effective
therapeutic option for lowering LDL-cholesterol (LDL-C) and
reducing the risk of major adverse cardiovascular events (6). Among these agents, evolocumab is
widely used in current clinical practice, and reduces LDL-C by ~60%
at the end of the dosing interval, with a mean reduction of 65-68%
maintained throughout the interval (7,8).
Optical coherence tomography studies have demonstrated that, in
patients with non-ST-segment elevation myocardial infarction
(NSTEMI), the addition of evolocumab to background statin therapy
significantly improves the compositional characteristics of
coronary plaques. Compared with the placebo group, patients treated
with evolocumab exhibited a greater increase in minimum fibrous cap
thickness (+42.7 µm vs. +21.5 µm; P=0.015), along with significant
reductions in maximum lipid arc and macrophage index (P=0.04).
Furthermore, in lipid-rich plaque regions, evolocumab showed a more
pronounced trend toward plaque stabilization, and intravascular
ultrasound (IVUS) assessment revealed a greater reduction in
percent atheroma volume (-2.29% vs. -0.61%; P=0.009). These
findings suggest that the addition of evolocumab to statin therapy
following acute coronary syndrome promotes coronary plaque
stabilization and regression, supporting a mechanistic basis for
reducing future cardiovascular events through favorable
modification of plaque composition (9). Tafolecimab (SINTBILO®) is a
subcutaneously administered monoclonal antibody targeting PCSK9
that was developed by Innovent Biologics (Suzhou) Co., Ltd. and was
approved in China in 2023 for adults with primary hyperlipidemia,
including heterozygous familial hypercholesterolaemia and
non-familial hypercholesterolemia, or with mixed dyslipidemia whose
LDL-C remains above target despite moderate- or high-intensity
statin therapy. Although tafolecimab markedly lowers LDL-C, total
cholesterol and apolipoprotein B, it remains unclear whether it
also exerts direct anti-foam-cell and anti-inflammatory effects on
macrophages residing within the vascular wall beyond its systemic
lipid-lowering effects (10).
In the present study, in vitro experiments
were conducted using an ox-LDL-induced foam-cell model in RAW264.7
macrophages. In total, two control groups, namely a blank control
group and a model control group, together with six experimental
groups treated with low, medium or high doses of tafolecimab or
evolocumab were established. Intracellular lipid accumulation was
assessed by Oil Red O staining and LDL-C assay. Western blot
analysis was performed to evaluate changes in the expression of key
proteins involved in cholesterol metabolism, including SR-A and
ABCG1, as well as the phosphorylation status of components of the
nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK)
signaling pathway, including NF-κB p65 and phosphorylated (p)-p38.
The secretion levels of the inflammatory cytokines tumor necrosis
factor-α (TNF-α) and interleukin-6 (IL-6) were measured by
enzyme-linked immunosorbent assay (ELISA). The present study aimed
to systematically elucidate the effects of tafolecimab on
macrophage foam-cell formation and inflammation, investigate the
underlying molecular mechanisms with a focus on cholesterol
metabolism and related signaling pathways, and perform a parallel
comparison with evolocumab to provide a stronger experimental and
theoretical basis for the clinical application of tafolecimab.
Materials and methods
Cell line, reagents and
instruments
The murine monocyte-macrophage cell line RAW264.7
was obtained from iCell. Tafolecimab and evolocumab were supplied
by Innovent Biologics, Inc. Ox-LDL was purchased from Yiyuan
Biotechnologies (cat. no. YB-002). The Oil Red O staining kit was
purchased from Sigma-Aldrich; Merck KGaA (cat. no. O0625-25g). The
LDL-C and total cholesterol assay kits (cat. nos. A113-1-1 and
A111-1-1, respectively) were obtained from Nanjing Jiancheng
Bioengineering Institute. Primary antibodies against SR-A (cat. no.
17858-1-AP), ABCG1 (cat. no. 13578-1-AP), p38 (cat. no.
14064-1-AP), p-p38 (cat. no. 28796-1-AP), NF-κB p65 (cat, no.
10745-1-AP), p-NF-κB p65 (cat. no. 82335-1-RR), vinculin (cat. no.
26520-1-AP), tubulin (cat. no. 66031-1-Ig) and GAPDH (cat. no.
10494-1-AP) were purchased from Proteintech Group, Inc., and goat
anti-rabbit mouse igG-HRP (cat. no. M21003) was obtained from
Abmart. The enhanced chemiluminescence (ECL) detection kit was
provided by Shanghai Yeasen Biotechnology Co., Ltd. (cat. no.
36222ES60). TNF-α and IL-6 ELISA kits were obtained from Uping Bio;
Hangzhou Zhenyoupin Biotechnology Co., Ltd. (cat. nos. SYP-M0036
and SYP-M0031, respectively). CO2 incubators, microplate
readers, and western blot electrophoresis and transfer systems were
provided by the Institute of Pediatrics, Women and Children's
Medical Center, Guangzhou Medical University (Guangzhou,
China).
Cell culture and treatment groups
RAW264.7 cells were subjected to mycoplasma testing
and short tandem repeat profiling. RAW264.7 cells were maintained
in DMEM supplemented with 10% fetal bovine serum
(BIOEXPLORER®; Guangzhou Yufeng Biotechnology Co., Ltd.)
at 37˚C in a humidified with 5% CO2. The experimental
design comprised a blank control group, a model group, and
tafolecimab or evolocumab treatment groups. In the blank control
group, cells were cultured under standard conditions. In the model
group, cells were cultured in serum-free medium for 24 h, followed
by exposure to 100 µg/ml ox-LDL for 24 h. For the tafolecimab
groups, cells were first cultured in serum-free medium for 24 h and
then pretreated with tafolecimab at 5, 10 or 20 µmol/l for 24 h.
Subsequently, 100 µg/ml ox-LDL was added without removing the
drug-containing medium, and the cells were co-incubated with
tafolecimab and ox-LDL for a further 24 h. The evolocumab groups
were treated using the same protocol. The concentrations of
tafolecimab and evolocumab (5, 10 and 20 µmol/l) were selected
based on preliminary dose-finding experiments in RAW264.7 cells
(11,12), which showed robust,
concentration-dependent effects on foam-cell formation in the
absence of detectable cytotoxicity. Although these concentrations
fall within the order of magnitude of free antibody levels that may
be achievable in patients receiving therapeutic doses, they were
selected primarily for exploratory mechanistic studies rather than
for establishing direct clinical equivalence.
Oil Red O staining
Cells were seeded into 24-well plates at a density
of 3x106 cells per well and treated according to their
corresponding experimental group. After treatment, the cells were
washed with PBS, fixed with 4% paraformaldehyde for 20 min at room
temperature. After fixation, cells were washed three times with
PBS. Oil Red O stock solution was prepared by dissolving 0.25 g Oil
Red O powder in 50 ml isopropanol and stored away from light. The
working solution was mixed with the stock solution and distilled
water at a volume ratio of 3:2 and filtered before use. Cells were
incubated with the working solution at room temperature in the dark
for 20 min. After discarding the staining solution, each well was
rinsed with 60% isopropanol for 30 sec. Following removal of the
60% isopropanol solution, hematoxylin was added for 1 min for
counterstaining. Foam-cell formation was assessed by light
microscopy on the basis of red intracellular lipid-droplet
accumulation, and representative images were acquired. Quantitative
analysis of Oil Red O-positive lipid droplets was conducted using
ImageJ software (version 1.54u7; National Institutes of
Health).
Measurement of intracellular
cholesterol content
Cells were seeded into 6-well plates at a density of
1x106 cells per well, and after the designated
treatments, were harvested. The prepared cell suspension was
collected and centrifuged at 165 x g for 10 min at 25˚C, after
which the supernatant was discarded and the cell pellet was
retained. The pellet was washed twice with PBS, followed by
centrifugation at 165 x g for 10 min at 25˚C, the supernatant was
then removed again to reserve the cell pellet. Cells were lysed
with 2% Triton X-100 (Glpbio Technology) on ice for 40 min. The
lysate was directly subjected to detection without centrifugation.
After incubation at 37˚C for 10 min, the absorbance of each well
was measured at a wavelength of 500 nm. Statistical analysis was
performed using GraphPad Prism version 10.1.2 (Dotmatics).
Western blot analysis of protein
expression
Following the corresponding assigned treatments,
cells were washed with ice-cold PBS and lysed in RIPA lysis buffer
(Thermo Fisher Scientific, Inc.), supplemented with 1% protease and
phosphatase inhibitors on ice for 30 min. The lysates were then
centrifuged at 12,000 x g for 15 min at 4˚C to collect the
supernatant. Total cellular protein concentration was quantified
using a BCA protein assay kit (Thermo Fisher Scientific, Inc.).
Equal amounts of total cellular protein (10 µg per lane) were
separated by 10% SDS-PAGE electrophoresis and subsequently
electrotransferred onto PVDF membranes. Membranes were blocked with
5% non-fat milk at room temperature for 1 h, and then the membranes
were incubated with primary antibodies against SR-A, ABCG1, NF-κB
p65, p-p65, p38, p-p38, vinculin, tubulin and GAPDH, followed by
HRP-conjugated secondary antibodies. All primary antibodies were
diluted at 1:2,000 and incubated with membranes overnight at 4˚C.
The corresponding HRP-conjugated secondary antibodies were diluted
at 1:5,000 and incubated for 1 h at room temperature.
Immunoreactive bands were visualized using ECL, and band
intensities were quantified using ImageJ software (version 1.54u7).
Target protein expression was normalized to the appropriate loading
controls GAPDH, tubulin and vinculin.
ELISA for detecting inflammatory
cytokines
Cell culture supernatants were collected, and the
concentrations of TNF-α and IL-6 were quantified using ELISA kits
according to the manufacturer's instructions.
Statistical analysis
All data were analyzed using GraphPad Prism (version
10.1.2; Dotmatics) and are presented as the mean ± standard
deviation. Comparisons among multiple groups were performed using
one-way analysis of variance (ANOVA), followed by Dunnett's post
hoc test for pairwise comparisons against the control group
(model). P<0.05 was considered to indicate a statistically
significant difference. All experiments were performed with three
independent biological replicates.
Results
Tafolecimab inhibits macrophage foam
cell formation
Oil Red O staining revealed that cells in the blank
control group retained normal morphology and showed no evident red
intracellular lipid droplets, whereas cells in the model group
exhibited marked cytoplasmic lipid-droplet accumulation, indicative
of foam-cell formation. Relative to the model group, all
tafolecimab pretreatment markedly reduced intracellular
lipid-droplet accumulation in a dose-dependent manner (Figs. 1A-E and 2A). Comparable inhibitory effects were
observed in the evolocumab-treated groups (Figs. 1F-J and 2B).
Tafolecimab reduces intracellular
cholesterol accumulation
The findings of the LDL-C assay were consistent with
those obtained by Oil Red O staining. Cellular LDL-C levels were
markedly increased in the model group relative to the blank control
(P<0.05). Tafolecimab reduced intracellular LDL-C content in a
dose-dependent manner (Fig. 3), and
the extent of this reduction was comparable to that observed with
evolocumab, suggesting that both agents exert similar inhibitory
effects on intracellular LDL-C accumulation (Fig. 3).
Tafolecimab regulates the expression
of cholesterol-metabolism-related proteins
As shown in Fig. 4,
ox-LDL markedly altered the expression of key regulators of
cholesterol influx and efflux in RAW264.7 macrophages. Relative to
the blank control group, ox-LDL stimulation significantly reduced
ABCG1 expression (P<0.01) and increased SR-A expression
(P<0.05), which is consistent with a shift toward a
cholesterol-accumulating phenotype.
Pretreatment with tafolecimab for 24 h, followed by
co-incubation with ox-LDL, significantly and dose-dependently
upregulated ABCG1 and downregulated SR-A relative to the ox-LDL
model group (P<0.05 for all concentrations; Fig. 4C and D). Evolocumab produced a highly similar
pattern of regulation, and the magnitude of its effects was
comparable to that of tafolecimab across the tested concentrations
(Fig. 4E and F). These findings suggest that both PCSK9
inhibitors promote a cholesterol-efflux-favouring profile in
ox-LDL-treated macrophages through coordinated modulation of ABCG1
and SR-A expression.
Tafolecimab suppresses the activation
of the NF-κB and MAPK signaling pathway
To further investigate the underlying mechanisms,
the activation status of key signaling pathways was assessed.
Ox-LDL markedly increased the phosphorylation of MAPK p38 and NF-κB
p65. By contrast, pretreatment with tafolecimab suppressed the
phosphorylation of these proteins, which is consistent with
inhibition of NF-κB and MAPK signaling. Similarly, evolocumab also
reduced the phosphorylation levels of p38 and p65 (Fig. 5).
 | Figure 5Effects of tafolecimab and evolocumab
on p38 and p65 phosphorylation in ox-LDL-stimulated macrophages.
(A) Representative western blot images showing the protein
expression levels of p-p38, total p38, p-p65, and total p65 in
macrophages stimulated with ox-LDL and treated with tafolecimab or
evolocumab at indicated concentrations (5, 10, and 20 µmol/l).
Vinculin and tubulin were used as loading controls. Molecular
weights are indicated on the right. (B and C) Quantitative analysis
of (B) p-p38 (B) and (C) p-p65 protein levels, normalized to their
respective total proteins (p38 or p65) and expressed as relative
intensity compared with the model group. (D and E) Trend analysis
of relative (D) p-p38 and (E) p-p65 protein expression across
treatment groups. Data are presented as the mean ± standard
deviation from three independent experiments. Statistical analysis
was performed using one-way ANOVA followed Dunnett's post hoc test.
*P<0.05, **P<0.01 and
***P<0.001. ox-LDL, oxidized low-density lipoprotein;
p-p38, phosphorylated p38; p-p65, phosphorylated p65; Con, control
group; Mol, ox-LDL model group. |
Tafolecimab inhibits the secretion of
inflammatory cytokines
ELISA demonstrated that IL-6 and TNF-α (Fig. 6) levels in the culture supernatant
were significantly elevated in the model group relative to the
blank control group (P<0.001). Tafolecimab markedly reduced the
secretion of both cytokines in a dose-dependent manner
(P<0.001). As the positive control, evolocumab also
significantly downregulated the expression of IL-6 and TNF-α
(P<0.001).
Discussion
AS is a leading cause of global morbidity and
mortality, driving the pathogenesis of disabling peripheral artery
disease, stroke and myocardial infarction (13). Since its identification in the early
2000s, PCSK9 has emerged as a central regulator of cholesterol
homeostasis, and its favorable pharmacological profile has
underscored its immense therapeutic potential in the context of AS
(14). The present study provides
the first systematic demonstration of the pleiotropic mechanisms by
which tafolecimab attenuates macrophage foam-cell formation and
mitigates inflammatory responses. Mechanistically, it was found
that tafolecimab promotes a more favorable state of cholesterol
homeostasis by concurrently suppressing SR-A-mediated cholesterol
influx and enhancing ABCG1-mediated cholesterol efflux, thereby
shifting macrophages toward a cholesterol-efflux-promoting
phenotype (14-18).
Together with ATP-binding cassette subfamily A member 1 (ABCA1),
ABCG1 is a key ATP-binding cassette transporter that facilitates
cholesterol efflux from macrophages to HDL and other extracellular
acceptors. By limiting the accumulation of free and esterified
cholesterol, ABCG1 has a central role in preserving intracellular
cholesterol homeostasis and restraining foam-cell formation
(17). The tafolecimab-induced
upregulation of ABCG1 observed in the present study may thereby
contribute not only to reduced intracellular cholesterol burden,
but also to the reprogramming of macrophages towards an
anti-atherogenic, inflammation-resolving state (17,18).
Notably, the present study further delineated the upstream
signaling pathways induced by the molecular targets of tafolecimab.
The NF-κB and MAPK signaling pathways serve as core regulators of
inflammation and cellular stress responses (19-23).
Activation of NF-κB and MAPK signaling in lesional macrophages has
profound consequences for plaque biology. NF-κB-driven
transcription amplifies the production of pro-inflammatory
cytokines, including TNF-α and IL-6, which not only sustain local
inflammation but also impair endothelial nitric oxide
bioavailability, thereby exacerbating endothelial dysfunction and
promoting a pro-thrombotic, vasoconstrictive microenvironment. MAPK
signaling also plays a central role in regulating macrophage
survival, proliferation and the expression of matrix-degrading
enzymes, processes that can compromise fibrous-cap integrity.
Sustained activation of these pathways favors macrophage apoptosis
and secondary necrosis in the lipid core, expansion of the necrotic
core and thinning of the fibrous cap, ultimately increasing the
risk of plaque rupture and thrombosis. Therefore, the ability of
tafolecimab to attenuate NF-κB and MAPK activation and to reduce
TNF-α and IL-6 secretion in ox-LDL-treated macrophages may, in
principle, translate into improved endothelial function, reduced
necrotic core formation and enhanced plaque stability in
vivo (24).
Tafolecimab is a fully human monoclonal antibody
that neutralizes circulating PCSK9 within the extracellular
compartment. Canonically, PCSK9 binds to LDL receptors (LDLR) and
targets them for lysosomal degradation, thereby increasing
circulating LDL-C levels. In macrophages, however, PCSK9 appears to
exert a function that extends beyond LDLR reregulation. Previous
experimental evidence indicates that PCSK9 is expressed by
macrophages and can influence scavenger receptors, including SR-A,
cholesterol efflux transporters and pro-inflammatory signaling
pathways (25,26).
In this context, the effects of tafolecimab observed
in the present study are likely to be multifactorial. By
neutralizing PCSK9, tafolecimab may alter LDLR-dependent
lipoprotein uptake and intracellular cholesterol handling, while
also indirectly modulating SR-A and ABCG1 expression through
changes in cellular cholesterol burden and membrane composition. In
parallel, PCSK9 inhibition may directly suppress PCSK9-driven
pro-inflammatory signaling, thereby decreasing NF-κB/MAPK
activation and downstream cytokine release. Defining the relative
contributions of LDLR-dependent and -independent pathways will
require future studies incorporating PCSK9 knockdown or knockout
models and receptor-specific interventions.
In the present study, evolocumab was included as an
established comparator PCSK9 inhibitor. At equivalent
concentrations in vitro, tafolecimab and evolocumab exerted
broadly similar effects on foam-cell formation, cholesterol
handling and inflammatory signaling, indicating that the observed
responses are likely to be largely class-related. However,
individual PCSK9 monoclonal antibodies recognize distinct epitopes
and may differ in binding affinity, pharmacokinetic behaviour and
tissue distribution in vivo. In principle, such differences
could give rise to subtle qualitative or quantitative variations in
the modulation of PCSK9-LDLR interactions, as well as in other
PCSK9-dependent effects on vascular cells. Since the present in
vitro system does not enable rigorous pharmacokinetic or
epitope-specific comparisons, further structural and in vivo
studies will be required to establish whether tafolecimab confers
any advantages beyond its LDL-C-lowering efficacy. Several
limitations should be considered when interpreting the present
findings. First, all experiments were conducted in a single murine
macrophage-like cell line (RAW264.7). Although RAW264.7 cells are
widely used in atherosclerosis research, immortalized cell lines
cannot fully capture the phenotypic heterogeneity and functional
complexity of primary human monocyte-derived macrophages or
distinct lesional macrophage subsets. Validation in primary
macrophages and in vivo models of atherosclerosis will
therefore be essential. The current analyses focused on SR-A and
ABCG1 as representative mediators of cholesterol influx and efflux,
respectively, and on the NF-κB and MAPK signaling pathways as
central inflammatory pathways. However, foam-cell formation and
vascular inflammation are governed by a broader network of
receptors, transporters and signaling cascades, including CD36,
LOX-1, ABCA1, JNK, ERK and inflammasome-related pathways
components, which were not examined in the present study.
Additionally, the present study was limited to relatively
short-term (24 h) treatments and did not address the long-term
effects of tafolecimab on macrophage survival, apoptosis,
efferocytosis or necrotic core formation, all of which are major
determinants of plaque stability. Therefore, future studies in
animal models and human tissues will be needed to establish whether
the acute cellular effects observed in vitro translate into
sustained alteration in plaque burden, plaque composition and
clinical outcomes. These findings suggest that tafolecimab may
benefit high-risk patients with residual inflammatory risk who
continue to experience cardiovascular events despite achieving
target LDL-C levels. If validated in vivo, tafolecimab could
offer a dual benefit by addressing both lipid and inflammatory
risks to enhance plaque stability.
In summary, tafolecimab was shown to effectively
attenuate ox-LDL-induced macrophage foam-cell formation and
inflammatory responses. Mechanistically, tafolecimab ameliorated
ox-LDL alteration in cholesterol homeostasis by modulating the
expression of key cholesterol influx and efflux, while concurrently
suppressing NF-κB and MAPK inflammatory signaling. Collectively,
these findings provide mechanistic insights into the
anti-atherogenic effects of tafolecimab and support its potential
as a therapeutic strategy for AS.
Acknowledgements
Not applicable.
Funding
Funding: The present study was supported by the Xinhuo
Inheritance Special Scientific Research Fund (grant no. XHXC017),
the Hunan Provincial Natural Science Foundation (University Joint
Fund Project; grant no. 2025JJ90126), and the Special Research
Project of National Health Commission Capacity Building and
Continuing Education Center (grant no. GWJJZX20251007036), which
enabled the completion of key experiments in the present study.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
RL conceived the study, designed the overall
experimental protocol, led project planning and funding
acquisition, and was responsible for the final review and approval
of the manuscript. XY conducted the in vitro experiments,
performed systematic data integration and processing, and drafted
and revised the manuscript. XL made substantial contributions to
the conception and design of the study, and critically reviewed the
manuscript for important intellectual content. YD made substantial
contributions to the acquisition of experimental data, as well as
the formal analysis and interpretation of data. RL and XY confirm
the authenticity of all the raw data. All authors read and approved
the final manuscript.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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