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Suppression of oxLDL-Induced MMP-9 and EMMPRIN Expression by Berberine via Inhibition of NF-╬║B Activation in Human THP-1 Macrophages.

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THE ANATOMICAL RECORD 295:78–86 (2012)
Suppression of oxLDL-Induced MMP-9
and EMMPRIN Expression by Berberine
via Inhibition of NF-jB Activation in
Human THP-1 Macrophages
Department of Cardiology, First Affiliated Hospital, Wenzhou Medical College,
Wenzhou 325000, China
Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong
University School of Medicine, Shanghai 200011, China
Department of Cardiology, Xin Hua Hospital, Shanghai Jiaotong University School of
Medicine, Shanghai 200092, China
Upregulation of matrix metalloproteinases (MMPs) and extracellular
matrix metalloproteinase inducer (EMMPRIN) by macrophages leads to
atherosclerotic plaque rupture by degradation of the extracellular matrix.
NF-jB activation regulates many key inflammatory genes linked to atherosclerosis. In the present study, the function of berberine, a natural extract
from Rhizoma coptidis, on MMP-9 and EMMPRIN expression, the role of
NF-jB activation in oxLDL-stimulated macrophages, and the possible
mechanism in which NF-jB activation is involved were investigated.
Berberine inhibited the expression of MMP-9 and EMMPRIN at both
mRNA and protein levels. The phosphorylation of IjB-a and nuclear translocation of p65 protein were reduced by berberine, suggesting that NF-jB
activation was inhibited by berberine in oxLDL-stimulated macrophages.
Overall, berberine suppressed the expression of MMP-9 and EMMPRIN by
at least reducing partly the activity of NF-jB in oxLDL-induced macroC 2011 Wiley Periodicals, Inc.
phages. Anat Rec, 295:78–86, 2012. V
Key words: berberine; MMP-9; EMMPRIN;
stimulated macrophages
The stability of an atherosclerotic plaque determines
whether a patient will experience stable angina pectoris
or a life-threatening acute coronary syndrome (Shin
et al., 2003). Macrophage infiltration and expression of
matrix metalloproteinase-9 (MMP-9), degrading the
extracellular matrix, contribute to atherosclerotic plaque
instability (Galis et al., 1995; Kunte et al., 2008). This
finding has also been supported by in vivo studies showing that plasma levels of matrix metalloproteinases
(MMPs) can determine future coronary events (Kai
et al., 1998; Blankenberg et al., 2003).
Extracellular matrix metalloproteinase inducer (EMMPRIN) triggers the synthesis of MMP-9 in a paracrine or
autocrine manner (Zhou et al., 2005; Schmidt et al.,
2006). Increasing evidence shows that in response to certain proatherogenic stimuli such as oxLDL, EMMPRIN
is upregulated strongly in atherosclerosis-related cells,
including macrophages and coronary smooth muscle
cells (Major et al., 2002; Haug et al., 2004; Schmidt
et al., 2006). It also increases in activated platelets and
Grant sponsor: Science and Technology Commission of
Shanghai Municipality; Grant number: 08411966900; Grant
sponsor: Traditional Chinese Medicine of Zhejiang; Grant
number: 2010ZA085.
*Correspondence to: Changqian Wang, Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong
University School of Medicine, 639 Zhizaoju Road, Shanghai
200011, China. Fax: þ86-21-6313-6856.
Received 14 June 2010; Accepted 20 August 2011
DOI 10.1002/ar.21489
Published online 5 December 2011 in Wiley Online Library
mediated NF-jB activation by inducing the production
of MMP-9, IL-6, and TNF-a (Schmidt et al., 2008). This
evidence suggests that EMMPRIN plays a key regulatory role in the development of atherosclerosis.
EMMPRIN and MMP-9 can promote the instability of
atherosclerotic plaques. Therefore, hypothetically, the
inhibitors of EMMPRIN and MMP-9 are potential candidates for improving the development of atherosclerosis.
In this context, we are interested in the isoquinoline
alkaloid berberine. Berberine can be isolated from many
medicinal herbs such as Hydrastis canadensis (goldenseal), Cortex phellodendri (Huangbai), and Rhizoma
coptidis (Huanglian) (Ikram, 1975). When present as a
major ingredient, berberine can have pharmacological
effects on cancer (Anis et al., 2001) and bacterial diseases (Stermitz et al., 2000). Recently, berberine has
been found to have cholesterol- (Kong et al., 2004) and
glucose-lowering effects (Yin et al., 2008). Further, when
THP-1 cells differentiate into macrophages, berberine
inhibits MMP-9 and EMMPRIN expression (Huang
et al., 2009). However, the role of berberine on the
expression of MMP-9 and EMMPRIN and its possible
mechanism in oxLDL-stimulated macrophages remain
NF-jB plays a key role in atherosclerosis (Majdalawieh and Ro, 2010). A strong signal of active NF-jB can
be detected in macrophages and endothelial cells in the
aorta with evident atherosclerotic lesions (Brand et al.,
1996). NF-jB activation is believed to promote the
expression of some MMPs (Yokoo and Kitamura, 1996;
Mengshol et al., 2000) and several factors that mediate
various processes such as inflammation and thrombosis,
which are key events in atherogenesis (Brand et al.,
1997). This evidence proves the critical role of active
NF-jB in atherosclerosis. Interestingly, oxLDL is potentially capable of activating NF-jB in macrophages in culture systems as well as in atherosclerotic lesions
(Rajavashisth et al., 1995; Brand et al., 1997). Some
studies have also demonstrated that inhibition of NF-jB
abrogates macrophage recruitment to the atherosclerotic
lesions and attenuates the development of atherosclerosis (Majdalawieh and Ro, 2010). Briefly, in unstimulated
cells, the NF-jB canonical signaling pathway p65 is
localized predominantly in the cytoplasm and remains
inactivated through binding with its inhibitory protein
known as IjB-a. In the presence of stimuli with oxLDL,
IjB-a is phosphorylated and subsequently degraded,
which allows p65 to be liberated from IjB-a, and to be
translocated into a nucleus where it binds to a specific
sequence in the promoter of target genes, resulting in
increased gene expression, including MMP expression
(Yamamoto and Gaynor, 2004). Hence, to observe the
role of berberine in atherosclerosis, the effects of berberine on the expression of MMP-9 and EMMPRIN and on
the activity of NF- jB (p65, IjB-a) in oxLDL-stimulated
macrophages was investigated.
Fig. 1. Effects of berberine on the viability of macrophages. Macrophages were treated with indicated concentrations of berberine
(5–100 lM), and cell viability was assessed after 48 hr using MTT
assay. Cells incubated in a medium without berberine served as the
control variables and were considered 100% viable.
acquired from Sigma-Aldrich (St. Louis, MO). Trizol reagent for RNA isolation was purchased from Invitrogen.
Omniscript reverse transcriptase for first-strand cDNA
synthesis was obtained from Qiagen. A rabbit monoclonal antibody to b-actin (ab8227) was produced by Abcam
(Cambridge, UK). An EMMPRIN antibody was obtained
from Zymed (South San Francisco, CA). MMP-9,
phospho-IjB-a, and p65 antibodies were obtained from
Cell Signaling Technology (Danvers, MA). Lamin B antibodies were obtained from Sigma-Aldrich (St. Louis, MO).
NE-PER nuclear and cytoplasmic extraction reagents
were purchased from Pierce. All goat antirabbit secondary antibodies (Catalog No. A-21109) used in Western
blotting were from Invitrogen (Carlsbad, CA). A cellular
NF-jB translocation kit was purchased from Beyotime
Biotech. All other chemicals used for Western blotting
were of the highest purity commercially available.
Cell Culture and Treatment
Human monocytic cell line THP-1 was obtained from
American Type Culture Collection (Rockville, MD) and
was maintained at a density of 106/mL in RPMI 1,640
medium containing 10% FBS, 10 mM HEPES (Sigma–
Aldrich) and 1% pen/strep solution at 37 C in a 5% CO2
incubator. The cells were cultured in six-well plates for
48 hr in the presence of 100 nM PMA, which allowed
them to differentiate into adherent macrophages (Tsuchiya et al., 1982). The cells were pretreated with berberine (0–50 lM) for 1 hr prior to incubation with
oxLDL (50 lg/mL) for 24 hr. To observe berberine’s
inhibitory effects on the NF-jB signal pathway, cells
(2 106/mL) were pretreated with or without berberine
for 1 hr prior to incubation with oxLDL for the indicated
RPMI 1640 medium, fetal bovine serum, and penicillin/streptomycin (pen/strep, 10,000 U/mL each) were
purchased from GIBCO Company. Phorbol 12-myristate
13-acetate (PMA) was obtained from Calbiochem (San
Diego, CA). Dimethyl sulfoxide and berberine were
Determination of Cell Viability (MTT Assay)
MTT assay was used to assess the cytotoxicity of berberine on macrophages. After the indicated treatments,
the cells were incubated with 0.5 mg/mL 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
Fig. 2. Effects of berberine on MMP-9 expression in oxLDL-stimulated macrophages. MMP-9 mRNA and protein levels were measured
by real-time PCR and Western blot analysis. (A, B) Representative
Western blots of MMP-9 expression affected by berberine in different
concentrations and time courses. (C, D) Effects of berberine on MMP9 expression (mRNA and protein). Respective densitometric measure-
ment results are given. The band densities were measured by Quantity
one. Effects of berberine on MMP-9 mRNA expression. Data represent
mean S.D. (*) P < 0.05 and (**) P < 0.01 when compared with the
control group; (#) P < 0.05 and (##) P < 0.01 when compared with the
(**) marked group.
(Roche Applied Science) in a culture medium for an
additional 4 hr. Next, the blue formazan crystals of viable cells were dissolved in dindimethyl sulfoxide and
measured spectrophotometrically at 570 nm.
TTCGTTGT-30 (antisense), and 50 -fam-AACAGCGACACC
CACTCCTCCACC-tamra-30 (probe). The whole amplification course was initiated at 95 C for 10 min, followed by
40 cycles of 95 C for 15 sec, and 60 C for 45 sec. All
results were normalized against GAPDH. All real-time
PCRs were run in duplicate.
RNA Isolation, cDNA Synthesis, and TaqMan
Teal-Time PCR
Total RNA was extracted from oxLDL-stimulated
macrophages using Trizol reagent according to the
manufacturer’s instructions. Total RNA (2 lg) was
reverse-transcribed into cDNA using random primers.
The resultant cDNA was amplified by TaqMan real-time
polymerase chain reaction (PCR). The PCR reaction was
monitored directly by the Applied Biosystems 7500 RealTime PCR System with the following primer sequences:
(sense), 50 -CGCCATCTGCGTTTCCAA-30 (antisense), and
(antisense), and 50 -fam-CAGCACCAGCACCTCAGCCAC
GATG-tamra-30 (probe); and GAPDH, 5 0 -CCAGGTGGT
Protein Isolation and Western Blot Analysis
Protein was isolated from the cytoplasm and nuclear
fractions using NE-PER nuclear and cytoplasmic extraction reagents according to the manipulation for the analysis of IjB-a phosphorylation and nuclear p65/lamin B
levels. Protein isolation and Western blot analysis of the
cell lysates were performed as previously described
(Huang et al., 2008), except that the membranes were
probed with primary antibodies for rabbit antiMMP-9,
antiEMMPRIN, antiphospho-IjB-a, antilamin B, and
antip65 antibodies (diluted 1:1,000 in TBST) for 2 hr or
for rabbit antiactin (diluted 1:5,000 in TBST) for 1 hr,
followed by incubation with goat antirabbit secondary
antibodies labeled with far-red-fluorescent Alexa Fluor
680 dye. Briefly, all signals were detected by an Odyssey
imaging system (Li-cor). Densitometric analysis was
Fig. 3. Effects of berberine on EMMPRIN expression in oxLDLstimulated macrophages. EMMPRIN mRNA and protein expression
were determined by real-time PCR and Western blot analysis. (A, B)
Representative Western blots analysis of EMMPRIN expression. (C, D)
Effects of berberine on EMMPRIN expression (mRNA and protein).
Respective densitometric measurement results are given. The band
densities were measured by Quantity One. Data represent mean S.D. (*) P < 0.05 and (**) P < 0.01 when compared with the control
group; (#) P < 0.05 and (##) P < 0.01 when compared with the (**)
marked group.
again performed using Quantity
the signals.
Statistical Analysis
(Bio-Rad) to scan
Confocal Laser Scanning Fluorescence
Microscopy of NF-jB
Cells were seeded in a six-well tissue culture plate
and pretreated in the presence or absence of 25 lM 1 hr
prior to incubation with oxLDL for the indicated times
(1, 2, 3, and 6 hr). The cells were immunofluorescencelabeled using a cellular NF-jB translocation kit (Beyotime Biotech) according to the manufacturer’s protocol.
Briefly, after washing and fixing, the cells were incubated with a blocking solution at 4 C overnight and then
with the NF-jB p65 antibody for 2 hr. After washing
three times, a rabbit IgG antibody conjugated with Cy3
was added and incubated for 1 hr. To stain the nucleus,
the cells were then incubated with DAPI for 5 min. The
activation of NF-jB p65 was visualized with a confocal
laser scanning microscope (FluoViewTM FV1000, Olympus) at excitation wavelengths of 350 nm for DAPI and
540 nm for Cy3. The red and blue images were overlaid
to create a two-color image in which purple fluorescence
indicated the areas of colocalization.
The results were expressed as mean S.D. Differences were compared by one-way ANOVA (LSD, S-N-K,
Dunnet) using SPSS 11.0 software. Statistical significance was defined as P < 0.05. All experiments were
performed at least three times.
Effects of Berberine on Cell Viability
MTT assay was used to evaluate the effect of berberine
on the viability of the macrophages. As shown in Fig. 1, a
concentration of berberine ranging from 5 to 75 lM
caused no significant reduction (about 5–10%) in cell viability. Therefore, a berberine dose at or lower than 75 lM
was considered to be noncytotoxic, and doses ranging
from 5 to 50 lM were used in subsequent experiments.
Reduction of MMP-9 Levels by Berberine in
oxLDL-Stimulated Macrophages at Both mRNA
and Protein Levels
To determine whether berberine has effects on MMP-9
at the mRNA and protein levels, the macrophages were
Fig. 4. Effects of berberine on phosphorylated IjB-a (p-IjB-a) and
nuclear protein p65 expression in oxLDL-stimulated macrophages.
Cells were pretreated with vehicle or berberine (25 lM) for 1 hr, followed by oxLDL for 1, 2, 3, and 6 hr. The cell lysates were collected
for Western blotting. (A) Effect of berberine on p-IjB-a expression. (B)
Effect of berberine on p65 expression (p65 translocation).
(C, D) Respective densitometric measurement results of p-IjB-a and
p65. b-actin and lamin B expression was used for protein level normalization. Data represent mean S.D. (*) P < 0.05 and (**) P < 0.01
when compared with the control group; (#) P < 0.05 and (##) P < 0.01.
pretreated with the indicated concentration of berberine
for 1 hr, followed by a culture with oxLDL for 24 hr. The
amounts of MMP-9 mRNA were determined by real-time
PCR, and the MMP-9 protein levels were quantified by
Western blotting. Berberine inhibited the expression of
MMP-9 both at protein and mRNA levels in a dosedependent manner (Fig. 2A,C). Macrophages, which
were stimulated by oxLDL, were treated with berberine
(25 lM) for 3, 6, and 12 hr. As depicted in Fig. 2B,D,
MMP-9 expression was reduced by berberine in a timedependent manner. Therefore, berberine reduced MMP-9
expression at both transcription and translation levels in
oxLDL-stimulated macrophages.
time-dependent manner (Fig. 3). These results indicate
that the downregulation of EMMPRIN by berberine is at
least partly responsible for the reduction of MMP-9
expression in oxLDL-stimulated macrophages.
Reduction of EMMPRIN by Berberine at Both
mRNA and Protein Levels in oxLDL-Stimulated
As MMP-9 expression is positively regulated by EMMPRIN (Zhou et al., 2005; Yoon et al., 2005) and because
berberine can apparently downregulate MMP-9 expression in oxLDL-stimulated macrophages, whether the inhibitory effect of berberine on MMP-9 expression might be
a consequence of the inhibition of EMMPRIN expression
in oxLDL-stimulated macrophages was examined next.
Consistently, the results show that berberine has a similar
effect on EMMPRIN at both protein and mRNA levels in
oxLDL-stimulated macrophages in a dose-dependent or
Significant Inhibition of NF-jB Activation by
Berberine in oxLDL-Stimulated Macrophages
One emerging concept is that as a major regulator,
NF-jB plays a role in MMP-9 (Yoo et al., 2002; Chase
et al., 2002; Lu and Wahl, 2005) and EMMPRIN (Hagemann et al., 2005) expression. Therefore, examining
whether the activation of NF-jB is also involved in the
inhibitory effect of berberine on oxLDL-stimulated macrophages is interesting. As shown in Fig. 4, the phosphorylation of IjB-a in cytoplasmic protein, as well as p65
in nuclear protein extraction was increased significantly
in macrophages after stimulation by oxLDL (50 lg/mL)
for 1, 2, 3, and 6 hr. In contrast, berberine (25 lM)
blocked partially the degradation of IjB-a and the nuclear translocation of p65 at indicated times. As shown
in Fig. 5, the same tendency was found; the stain levels
of p65 diminished in berberine-treated macrophages.
Berberine suppressed effectively the mRNA and
protein expression of both MMP-9 and EMMPRIN in
Fig. 5. Representative microphotographs showing the effect of berberine on the translocation of NF-jB p65 in oxLDL-treated macrophages. NF-jB localization was visualized by binding with a Cy3conjugated secondary antibody. Cells were then incubated with DAPI
to stain the nuclei. Microscopic images were obtained using a confocal laser scanning microscope (three independent experiments), and
the red area (representative of the area that contains p65) and blue
area (representative of the nucleus part that is DAPI conjugated)
images were overlaid to create a purple fluorescence in areas of
colocalization. In untreated macrophages, the NF-jB p65 subunit was
localized predominantly in the cytoplasm (control group). Cells stimulated with oxLDL only showed a significant translocation of p65 to the
cell nucleus. In cells pretreated with 25 lM berberine for indicated
times and exposed to 50 lg/L oxLDL for 1, 2, 3, and 6 hr, NF-jB p65
was retained significantly in the cytoplasm.
oxLDL-stimulated macrophages. Berberine can also suppress NF-jB activation induced by oxLDL in macrophages. These results suggest that berberine exerts its
inhibitory effect on both expressions of EMMPRIN and
MMP-9 by at least partly suppressing NF-jB activity in
oxLDL-induced macrophages.
Plaque vulnerability is a primary determinant in
thrombus and rupture-mediated complications, most
notably unstable angina and acute myocardial infarction.
Accumulating evidence now supports the concept that
MMPs contribute to plaque rupture or trigger acute coronary syndrome (Lusis, 2000; Libby, 2001). Blankenberg
et al. (2003) reported a strong association between plasma
levels of MMP-9 and a subsequent 4.1-year risk for fatal
coronary artery disease events among 1,127 subjects with
established coronary disease. Fiotti et al. (2008) showed
that the expression of MMP-9, except TIMP-1 or MMP-2,
increases in plaques caused by acute coronary syndrome.
Therefore, while conversely retarding extracellular matrix
destruction and subsequent rupture, the inhibitors of
MMP-9 may be a useful therapy to prevent plaque rupture or its clinical sequelae.
In the present study, berberine markedly inhibited
MMP-9 expression induced by oxLDL in macrophages.
More importantly, it also inhibited the expression of
EMMPRIN, which in turn caused the reduction in
MMP-9. Given the important roles of MMP-9 and EMMPRIN expression in the development of atherosclerosis
and the inhibitory effects of berberine on this expression,
we concluded that berberine may exert its beneficial
properties by stabilizing atherosclerotic plaque, thus
improving the development of atherosclerosis.
Berberine has been used to treat diarrhea and gastrointestinal disorders in Chinese traditional medicine
(Choi et al., 2003). Recently, Doggrell et al. (2005) and
Kong et al. (2004) described the cholesterol-lowering
property of berberine. In a clinical study, Yin et al.
(2008) found that berberine lowers blood glucose levels
effectively in patients with type 2 diabetes. Berberine
prevents oxLDL-induced cellular dysfunction (Hsieh
et al., 2007), and it is effective in reducing excess body
weight (Lee et al., 2006). Therefore, berberine has
known properties for diminishing many of the major
risk factors for atherosclerosis, such as hyperlipidemia,
diabetes, and overweight. It is also notable for its antiinflammatory effects that inhibit the production of TNF-a,
MCP-1, and COX-2 expression (Chen et al., 2008; Guo
et al., 2008). A recent study reported that berberine prevents the formation of foam cells from macrophages by
enhancing LXRa-ABCA1-dependent cholesterol efflux
(Lee et al., 2010). These results provide evidence that
berberine has a beneficial effect on the prevention of
oxLDL is implicated in many proatherogenic events,
such as an increase in the expression of MMP-9 and
EMMPRIN, as seen in the present study. It can also
activate the nuclear transcription factor NF-jB at indicated times in macrophages (Rajavashisth et al., 1995;
Brand et al., 1997). Recent studies have shown that
NF-jB activation (nuclear translocation of p65), which
has been observed in human and experimental atherosclerosis (Brand et al., 1996, 1997; Hajra et al., 2000), is
enhanced in unstable coronary atherectomies (Wilson
et al., 2002) and is involved in the upregulated expression of proinflammatory factors such as MMPs, except
TIMP-1 (Monaco et al., 2004). Both the mutation of the
NF-jB binding sequence in the promoters of MMPs and
the overexpression of IjB-a protein are accompanied
significantly by reduced MMP production in macrophages (Monaco et al., 2004; Ogawa et al., 2004). Therefore, the inhibition of NF-jB activation will impede the
progress of atherosclerosis. In fact, the suppression of
NF-jB activity by blocking IjB degradation results in
significantly smaller atherosclerotic lesions as compared
with those in control mice (Wolfrum et al., 2007).
Several studies have also demonstrated the positive
correlation between NF-jB activity and the incidence of
myocardial infarction (Thiemermann, 2004; Majdalawieh
and Ro, 2010). These results suggest that NF-jB is a
promising therapeutic target for reducing the risks of
The current study demonstrates that berberine
reduces the phosphorylation of IjB-a in the cytoplasm
(blocking IjB-a degradation) and suppresses the nuclear
translocation of p65 induced by oxLDL in macrophages,
indicating that NF-jB activation is inhibited by berberine. The same tendency is observed in the stain of NFjB p65 nucleus translocation. Collectively, berberine
suppresses not only MMP-9 and EMMPRIN expression
but also NF-jB activation. Further, the activation of
NF-jB is responsible for MMP-9 expression. Therefore,
in oxLDL-stimulated macrophages, the inhibitory effect
of berberine on MMP-9 and EMMPRIN expression is
at least partly associated with the downregulation of
NF-jB activation.
NF-jB activation is involved in EMMPRIN expression (Hagemann et al., 2005). As a novel platelet receptor, EMMPRIN in turn activates NF-jB (Schmidt et al.,
2008), suggesting that a positive feedback between
EMMPRIN and NF-jB exists. That is, the upregulation
of EMMPRIN expression regulates more NF-jB-related
inflammatory cellular activities (e.g., IL-6 and TNF-a.)
than only MMP activity. On the other hand, berberine
may play its multiple roles (as a potential inhibitor of
EMMPRIN and NF-jB) in regulating associated
inflammatory genes linked to atherosclerosis and in
exerting its protective effect to stabilize atherosclerostic
In conclusion, berberine inhibits the upregulated
expression of MMP-9 and EMMPRIN induced by
oxLDL in macrophages through the suppression of NFjB translocation into the nucleus. The downregulation
of MMP-9 and EMMPRIN stabilizes atherosclerotic plaque, so our results provide evidence that berberine
reduces inflammatory responses and thereby mitigates
plaque development. However, the effects of berberine
in vivo require further study using animal models of
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expressions, induced, inhibition, activation, thp, human, macrophage, emmprin, berberine, suppression, oxldl, via, mmp
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