REVIEW

published: 17 March 2021

doi: 10.3389/fphar.2021.631100

A New Therapeutic Candidate for

Cardiovascular Diseases: Berberine
Yun Cai 1†, Qiqi Xin 2,3†, Jinjin Lu 4, Yu Miao 2,3, Qian Lin 5*, Weihong Cong 2,3* and Keji Chen 2,3
1
Doctoral Candidate, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China, 2Laboratory of
Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China, 3National Clinical
Research Center for Chinese Medicine Cardiology, Beijing, China, 4Dongfang Hospital of Beijing University of Chinese Medicine,
Beijing, China, 5Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, China

Cardiovascular diseases (CVD) are the leading cause of death in the world. However, due
to the limited effectiveness and potential adverse effects of current treatments, the long-
term prognosis of CVD patients is still discouraging. In recent years, several studies have
found that berberine (BBR) has broad application prospects in the prevention and
treatment of CVD. Due to its effectiveness and safety for gastroenteritis and diarrhea
caused by bacterial infections, BBR has been widely used in China and other Asian
Edited by:
Konrad Urbanek, countries since the middle of the last century. The development of pharmacology also
Magna Græcia University of provides evidence for the multi-targets of BBR in treating CVD. Researches on CVD, such
Catanzaro, Italy
as arrhythmia, atherosclerosis, dyslipidemia, hypertension, ischemic heart disease,
Reviewed by:
Hermann Toplak,
myocarditis and cardiomyopathy, heart failure, etc., revealed the cardiovascular
Medical University of Graz, Graz, ST, protective mechanisms of BBR. This review systematically summarizes the
Austria pharmacological research progress of BBR in the treatment of CVD in recent years,
Suowen Xu,
University of Science and Technology confirming that BBR is a promising therapeutic option for CVD.
of China, China
Keywords: berberine, cardiovascular diseases, natural product, therapeutic effects, safety
*Correspondence:
Qian Lin
[email protected]
Weihong Cong INTRODUCTION
[email protected]
†
These authors have contributed
Cardiovascular diseases (CVD) are the leading cause of death in the world, including arrhythmia,
equally to this work atherosclerosis, myocardial infarction, hypertension, hyperlipidemia, myocarditis and
cardiomyopathy, and heart failure. These diseases are the results of multiple pathological factors,
Specialty section: and their pathogenesis have not been fully elucidated (Mozaffarian et al., 2015; Xu et al., 2018a; Xu
This article was submitted to et al., 2018b; Timmis et al., 2018). The effects of the current treatment strategies for CVD, including
Cardiovascular and Smooth Muscle antiplatelet drugs, anticoagulants, angiotensin converting enzyme inhibitors, statins, beta blockers
Pharmacology, and nitrates, are still limited (Squizzato et al., 2017; Zhao et al., 2017; Blessberger et al., 2018), and the
a section of the journal potential adverse effects of some drugs impaired the long-term prognosis and life quality of patients.
Frontiers in Pharmacology
New drugs discovery and development are constantly being desired.
Received: 19 November 2020 Berberine (BBR), also known as Huang Lian Su, is an isoquinoline alkaloid. The chemical
Accepted: 08 February 2021
structure of BBR is shown in Figure 1, and its molecular structure is C20H18NO4 and molecular
Published: 17 March 2021
weight is 336.39 g/mol. It is present in the root, rhizome and stem bark of many medicinally
Citation: important plants, such as Hydrastis canadensis (goldenseal), Coptis chinensis Franch (Coptis or
Cai Y, Xin Q, Lu J, Miao Y, Lin Q,
goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis
Cong W and Chen K (2021) A New
Therapeutic Candidate for
aristata (tree turmeric) (Chen et al., 2012). The main forms of BBR’s clinical application are
Cardiovascular Diseases: Berberine. hydrochloride and sulfate. In the past, it was mostly used as a kind of antibiotic for intestinal
Front. Pharmacol. 12:631100. infections. In recent years, BBR has been found to exhibit biological activities including the reduction
doi: 10.3389/fphar.2021.631100 of blood sugar, regulation of lipids, as well as anti-arrhythmic and cardio-protective effects (Ye et al.,

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Cai et al. Berberine Applications in Cardiovascular Diseases

rectifier K+ channels/Kir2.1. Zhou et al. (2015) assessed the

effect of BBR on acetylcholine intravenous injection induced
AF model in rabbits. The results showed that BBR (1 mg/kg,
i.v.) significantly reduced the rate of acetylcholine-induced
persistent AF and terminated most of the acetylcholine-
induced AF, and BBR (2 mg/kg, i.v.) terminated AF by
prolonging the effective refractory period of atrium and the
action potential duration of atrial myocytes. The effects may
result from BBR prolonging atrial repolarization by blockading
the components of the delayed rectifying K+ current (Zhou et al.,
2015). Hua and Wang, 1994 also confirmed the effect of BBR on
K+ channels. The results showed that BBR was able to block
inward rectifier K+ channels and delay rectifier K+ channels, and
thereby prolong the action potential duration. Furthermore, Li
et al. (1995) showed that BBR (10 mg/kg) was able to reduce the
incidence of ventricle tachycardia (VT), shorten the VT duration,
inhibit Ca2+ inwards in at a high Ca2+ concentration in
FIGURE 1 | Chemical structure of berberine. Berberine has been found reperfusion-induced arrhythmias rats, and the results of
to exhibit biological activities including the reduction of blood sugar, regulation in vitro experiments showed that BBR (30 μmol/L) promoted
of lipids, as well as anti-arrhythmic and cardio-protective effects. With the
progress of modern pharmacological research, the properties of BBR in
Ca2+ inwards at a low Ca2+ concentration, indicating that BBR
the treatment of multiple disease have gradually been discovered. may have an effect against reperfusion-induced arrhythmia by
inhibiting Ca2+ channels. Meanwhile, BBR derivatives such as
p-chlorobenzyltetrahydroberberine chloride (Cui et al., 2003) and
dihydroberberine (Zhang et al., 1997) have also been confirmed
2009). As a natural product-derived drug with development
to have an effect on arrhythmia. In summary, BBR have effects
prospects, it has been widely used in China and other Asian
against ventricular and supraventricular arrhythmias, which
countries for its effectiveness and safety (Jin et al., 2016; Ju et al.,
might result from inhibiting K+ and Ca2+ currents.
2018). With the progress of modern pharmacological research,
the properties of BBR in the treatment of multiple diseases have
gradually been discovered. Thus, we reviewed the molecular
targets and development potential of BBR in the treatment ATHEROSCLEROSIS
of CVD.
Atherosclerosis (AS) is a chronic traumatic disease and the main
cause of various cardio-cerebrovascular diseases. Its pathology
starts from endometrial damage. The plaque is formed by local
ARRHYTHMIA deposition of lipids, complex carbohydrates, fibrous tissue, and
calcium. The pathogenesis of AS is complex. A current study has
Cardiac arrhythmia is the leading cause of sudden cardiac death. found that multiple factors including low density lipoprotein
Evidence from a retrospective clinical study showed that BBR cholesterol (LDL-C) oxidation, platelet adhesion, inflammation,
(1.2–2.0 g/d, p.o., 12 weeks) had the same efficacy as amiodarone macrophage activation, endothelial cell damage, and smooth
in the treatment of atrial fibrillation (AF), and no adverse effects muscle cell proliferation are closely related to the development
was observed (Zheng et al., 2017). The anti-arrhythmic effect of of AS (Spence, 2016). BBR was demonstrated to significantly
BBR was first demonstrated in 1989. The author established an lower the levels of tumor necrosis factor α (TNF-α) and
ischemic model by ligating the anterior descending coronary interleukin-6 (IL-6) in both serum of apolipoprotein E gene
artery in dog. The results showed that BBR could significantly knockout (Apo-/-E) mice (5 mg/kg/d, i.v., 12 weeks) and
inhibit the occurrence of ischemic ventricular arrhythmias supernatant of human umbilical vein endothelial cells
(Huang et al., 1989). In recent years, several studies have (HUVECs) (50 μmol/L). Furthermore, it decreased the
further confirmed the antiarrhythmic effect of BBR. To expression of visfatin protein in aorta and down-regulated the
evaluate the effects and mechanisms of BBR on arrhythmia, protein expression of p38 mitogen-activated protein kinase (p38
Cao et al. (2012) established an arrhythmia model by MAPK), c-Jun N- terminal kinases (p-JNK), and Bax while up-
stretching the heart of wistar rats with myocardial infarction. regulated the expression of Bcl-2 in HUVECs. The results of this
The results showed that BBR inhibited the occurrence of study indicated that BBR suppressed the inflammatory response
ventricular tachycardia by decreasing the prolongation of and reduced blood lipid levels possibly by inhibiting the p38
repolarization of single-phase action potential and reducing MAPK and JNK signaling pathways, which improve endothelial
the incidence of ventricular premature beats. Wang et al. dysfunction and prevent the occurrence of AS (Wan et al., 2018).
(2011) verified the antiarrhythmic effect of BBR (180 mg/kg/d, In a recent study, BBR (78 and 156 mg/kg, p.o., 12 weeks) reduced
i.g., 2 weeks) in myocardial infarction model in diabetic rats, and aortic reactive oxygen species (ROS) production and decreased
showed such effects may result from BBR regulating inward serum malondialdehyde (MDA), oxidized low-density

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Cai et al. Berberine Applications in Cardiovascular Diseases

FIGURE 2 | The summarization of effects and main signal pathways regulated by berberine in its organ-and tissue-protective effects from both in vivo and in vitri
studies. (↑: increase; ↓: decrease).

lipoprotein (ox-LDL) and IL-6 levels in an Apo−/−E mice model, study demonstrated that BBR (25 µmol/L) might reduce ox-LDL-
demonstrating that BBR may improve endothelial dysfunction by induced macrophage activation and down-regulate galectin-3
restoring endothelium-dependent vasodilation and attenuating expression by inhibiting the activation of NF-κB and AMPK
oxidative stress and inflammatory responses, thereby preventing signaling pathways. However, the clinical results of the same
AS (Tan et al., 2020). In addition, an evidence from 16S rRNA study showed that an additive 300 mg of BBR hydrochloride t.i.d.
sequencing showed that BBR (100 mg/kg, i.g., 13 weeks) treatment on top of standard therapy did not further reduce
significantly altered the community composition structure of plasma levels of galectin-3 in acute coronary syndrome patients
the gut microbiota by anti-inflammation and regulating undergoing PCI. This discrepancy between in vitro and clinical
glucose and lipid metabolism (Wu et al., 2020). An in vitro results is worth being further discussed (Pei et al., 2019). In a rat
experiment reported that BBR (25 µmol/L) was able to inhibit model, BBR (1–100 µmol/kg, i.v., 4 weeks) combined with
the expression of extracellular matrix metalloproteinase inducer atorvastatin calcium reduced the levels of serum total
(EMMPRIN) and matrix metalloprotein (MMP)-9 in cholesterol (TC), triglyceride (TG), and LDL-C. It also reduced
macrophages stimulated by ox-LDL, which inhibited the the levels of plasma endothelium ET-1 (ET1) and decreased the
progression of AS. The mechanism of action of BBR was expression of lectin-like oxidized low-density lipoprotein
possibly through the activation of NF-κB in macrophages, the receptor-1 (LOX1), which may prevent the transport of LOX1-
prevention of IκB-α degradation, and the inhibition of p65 in the mediated ox-LDL into macrophages to promote foam cell
cytoplasm from entering the nucleus, resulting in MMP-9 and formation (Chi et al., 2014). BBR (150 mg/kg/d, p.o.) reduced
EMMPRIN expression downregulation and AS plaque foam cells and macrophage infiltration, decreased TNF-α and IL-
stabilization (Huang et al., 2012). In-stent restenosis and 1β levels, upregulated LC3-II protein expression and
neoatherosclerosis after percutaneous coronary intervention downregulated P62 protein expression in the aortic tissues in
(PCI) are closely related to inflammatory response. Galectin-3 AS rats, indicating that BBR might inhibit plaque formation and
is an important regulatory factor of inflammation, which is attenuated the inflammatory response in aortic tissue by
mainly expressed in macrophages. The results of an in vitro promoting autophagy (Ke et al., 2020). BT1500M, a kind of

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Cai et al. Berberine Applications in Cardiovascular Diseases

TABLE 1 | Summary of the mechanisms of action of berberine in the treatment of CVD.

Disease Mechanisms

Arrhythmia Inhibits the activation of K+ current → Prolongs the effective refractory period of the atrium and the action potential duration of
the atrial myocytes → Reduces the incidence of ventricular premature beats and inhibit the occurrence of VTa Hua and Wang
(1994), Wang et al. (2011), Cao et al. (2012), Zhou et al. (2015). Inhibits Ca2+ current → Reduces the incidence of VT and
shorten the duration of VT →Treats reperfusion arrhythmia Li et al. (1995).
Atherosclerosis Inhibits the p38 MAPK and JNK signaling pathways → Inhibits the inflammatory response → Reduces blood lipids →
Improves endothelial dysfunction → Prevents ASb Wan et al. (2018) Inhibits the ROSc production and reduces MDAd, ox-
LDLe and IL-6f levels →Restores the endothelium-dependent vasodilation → Reduces the oxidative stress and inflammatory
response → Improves endothelial dysfunction → Prevents AS Tan et al. (2020) . Inhibits the NF-κB and AMPK signaling
pathways → Reduces macrophage activation → Inhibits foam cell formation → Reduces the levels of TCg, TGh, and LDL-Ci
Huang et al. (2012), Chi et al. (2014), Pei et al. (2019), Ke et al. (2020). Inhibits the expression of gp91phox protein and
enhance the activity of SODj → Reduces the superoxide levels → Inhibits oxidative stress → Prevents AS Sarna et al., (2010).
Inhibits the activation of ERK1/2 and the phosphorylation of AKT → Inhibits smooth muscle cell proliferation and migration →
Prevents AS and arterial restenosis Cho et al. (2005), Lee et al. (2006). Activates the PPARα-NOk signaling pathway/Inhibitis
the PI3K signaling pathway/Inhibits the PDI/MAPK/ERS system → Inhibits VSMCl proliferation Ma et al. (2015), Qiu et al.
(2017), Wang et al. (2020).
Hyperlipidemia Regulates the PCSK9-LDLR pathway → Reduces the level of LDLR protein in the liver → Reduces the plasma
concentrations of LDL-C, TG, and TC Xiao et al. (2012) Regulates the HNF-4α-miR122 pathway → Reduces
gluconeogenesis and lipid metabolism changes in the liver Wei S et al. (2016). Regulates the AMPKα-SREBP pathway →
Prevents olanzapine-induced lipid metabolism disorders Li et al. (2016).
Hypertension Increases the expression of NO → Promotes vasodilation → Maintains arterial elasticity and improves endothelial function
Zhang et al. (2018), Zhang et al. (2020). Inhibits the TRPV4 channels → Relaxes the vascular smooth muscle → Treats
hypertension and vascular aging Ueda et al. (2011), Wang et al. (2015a). Inhibits the MyD88-TLR4 pathway → Inhibits
endothelial apoptosis → Protects the vascular endothelium from damage Chung et al. (2004), Romero et al. (2011), Wang
and Ding (2015). Inhibits the CXCR4/JAK-2 signaling pathway → Protects endothelial cells Sainz and Sata (2007), Shao et al.
(2018). Activates the AMPK pathway → Inhibits endoplasmic reticulum stress in endothelial cells → Protects vascular
function Schröder and Kaufman (2005) Liu et al. (2015).
Ischemic heart disease Regulates the activity of AMPK in non-ischemic and ischemic regions of the heart → Reduces infarct areas during IRm injury
→ Improves cardiac function Chang et al. (2012) Increases the expression of miR-29b → Activates Akt in endothelial cells →
Promotes the proliferation and migration of endothelial cells → Improves myocardial remodeling Van der Laan et al. (2009),
Zhu et al. (2017) Activates the AMPK, PI3K-Akt-eNOS, Notch1/Hes1-PTEN/Akt, AK2/STAT3, and Smad7 pathways →
Reduces apoptosis → Reduces MI/Rn injury Chen et al. (2014), Yu et al. (2015), Zhao et al. (2016), Yao et al. (2018) Activates
the SIRT1 pathway → Reduces oxidative stress and cardiac inflammation → Reduces MI/R injury Yu et al. (2016) Regulates
the HIF-1α/BNIP3 pathway → Promotes mitochondrial autophagy, promotes cardiomyocyte proliferation, and inhibits
cardiomyocyte apoptosis → Reduces MI/R injury Zhu et al. (2020). Inhibits caspase-3 protein expression → Increases
VEGFo, FGF2p and TSP-1q expression → Reduces myocardial infarct size Banaei et al. (2020).
Myocarditis and cardiomyopathy Inhibits the p38 MAPK and JNK pathway → Inhibits CVB3r replication → Inhibits macrophage infiltration and pro-
inflammatory factors production → Reduces cardiac injury Dai et al. (2017), Dai et al. (2020b) Inhibits the Th17/Th1 cell
differentiation → Improves left ventricular function → Improves EAMsLiu et al. (2016) Increases the Sirt3 protein levels →
Inhibits caspase 9 and 3-like activation → Attenuates cardiotoxicity Coelho et al. (2017) Inhibits the elevation of intracellular
Ca2+ → Alleviates mitochondrial dysfunction → Decreases CKt, CK-MBu and MDA levels and increases SOD and CATv
levels → Improves cardiac dysfunction Xiong et al. (2018) Upregulates of SIRT1 and downregulates the p66shc expression
→ Inhibits the ROS production, apoptosis and mitochondrial damage → Improves cardiac dysfunction Wu et al., (2019).
Increases the cardiac AMPK and AKT activity and inhibits GSK3β activity → Inhibits cardiac fibrosis → improves cardiac
function Chang et al. (2015).
Heart failure Reduces the end-diastolic pressure of the right atrium and left ventricle, increases the left ventricular ejection fraction, and
decreases the arteriovenous oxygen difference → Reduces the incidence of ventricular arrhythmias → Improves quality of life
Marin-Neto et al. (1988), Zeng et al. (2003) Decreases the Ca2+ levels in myocardial cells → Decreases the left ventricular
end-diastolic pressure Zhang et al. (2008) Regulates the mTOR pathway → Inhibits the phosphorylation of ERK1/2 and p38
→ Enhances autophagy and inhibits endoplasmic reticulum stress → Prevents myocardial hypertrophy and apoptosis Li
et al. (2014), Hashemzaei et al. (2017) Activates the Pak1 pathway → Inhibits the upregulation of Fbxo32 → Treats
myocardial hypertrophy Tsui et al. (2015) Upregulates the PINK1/Parkin-mediated mitochondrial autophagy → Inhibits the
cardiomyocyte apoptosis and mitochondrial damage → Improves the cardiac dysfunction and myocardial hypertrophy
Abudureyimu et al. (2020).

a, ventricular tachycardia; b, Atherosclerosis; c, reactive oxygen species; d, malondialdehyde; e, oxidized low-density lipoprotein; f, interleukin-6; g, Total cholesterol; h, Triglyceride; i, LDL
cholesterol; j, superoxide dismutase; k, Nitric oxide; l, vascular smooth muscle cells; m, Ischemia-reperfusion; n, myocardial ischemia/reperfusion; o, vascular endothelial cell growth factor;
p, fibroblast growth factor-2; q, platelet response factor-1; r, coxsackievirus B3; s, experimental autoimmune myocarditis; t, creatine kinase; u, creatine kinase isoenzyme; v, catalase.

BBR-entrapped micelle, increased BBR deposition in liver and 2020).The development of oxidative stress is also associated
adipose by 107.6 and 172.3%, respectively. BT1500M (BBR, with the pathogenesis of AS. BBR can selectively inhibit the
100 mg/kg/day, i.p., 5 months) showed anti-atherosclerotic expression of gp91phox protein and enhance the activity of
efficacy in high-fat diet-fed Apo−/−E mice in vivo and in superoxide dismutase, thereby reducing the level of superoxide
adipocytes and macrophages AS models in vitro (Ma et al., produced by NADPH oxidase in LPS-stimulated macrophages,

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Cai et al. Berberine Applications in Cardiovascular Diseases

which may play a role in the prevention and treatment of AS the development of cardio-cerebrovascular diseases. It has been
(Sarna et al., 2010). confirmed in animal studies and clinical trials that BBR could
Neointimal hyperplasia (NH), is the universal response of the reduce blood lipid levels (Wang and Zidichouski, 2018).
vessels to injury which is manifested by abnormal migration and Proprotein convertase subtilisin/kexin9 type (PCSK9) is an
proliferation of vascular smooth muscle cells within the intima, enzyme that mediates LDL receptor (LDLR) degradation.
accompanied by deposition of new extracellular matrix. Endotoxin (LPS) can stimulate PCSK9 expression, reduce the
Histologically, NH is similar to AS but consists almost entirely of level of LDLR protein in liver, and increase TC, TG, and LDL-C
smooth muscle cells (approximately 20%) and newly synthesized levels while decrease HDL-C level, which can be antagonized by
extracellular matrix (ECM) (approximately 80%), and NH is the BBR through the up-regulation of LDLR mRNA expression.
leading cause of vessel restenosis in both medium term and long Moreover, BBR (10 or 30 mg/kg/d, i.g., 4 weeks) can down-
term (McMonagle, 2020). With respect to inhibiting the regulate PCSK9 expression to reduce the plasma
proliferation of smooth muscle cells, a study reported that BBR concentrations of LDL-C, TG and TC in mice. Therefore, BBR
(10 μmol/L) may inhibit the activation of extracellular signal- may inhibit LPS-induced dyslipidemia by regulating the PCSK9-
regulated kinases (ERKs) by inhibiting the production of LDLR pathway (Xiao et al., 2012). Hepatocyte nuclear factor 4α
intracellular reactive oxygen species (ROS), which inhibits ERK1/ (HNF-4α) is a key transcription factor for hepatocyte
2 activation and therefore suppresses the proliferation and migration differentiation, and miR122 is the main microRNA in liver
of vascular smooth muscle cells (VSMC) (Cho et al., 2005). It was that participates in lipid and glucose metabolism. BBR
confirmed in a rat carotid artery injury model that BBR (100 µg/kg/ attenuated TC, TG and LDL-C and increased HDL-C in high-
d, i.v., 4 weeks) may delay or partially inhibit protein kinase B (Akt) fat diet-induced diabetic mice. In experimental animals, a high
phosphorylation, thereby inhibiting the proliferation and migration dose of BBR (160 mg/kg, i.p.) appeared more effective compared
of VSMCs induced by angiotensin II and heparin-binding epidermal to the lower dose BBR (40 mg/kg, i.p.) in improving the lipid
growth factor (Lee et al., 2006). Several recent studies have confirmed profiles. In addition, the presence of BBR (10 μmol/L) attenuated
the role of BBR in inhibiting VSMC proliferation from several angles. the elevation of HNF-4α protein and miR122 expression in
BBR (30 μmol/L) inhibited angiotensin IV-induced VSMC palmitate (PA)-incubated HepG2 cells. The above data
proliferation by activating the PPARα-nitric oxide (NO) signaling indicated that BBR treatment could reduce the dysregulation
pathway (Qiu et al., 2017). BBR (100 µmol/L) may also restrain the of gluconeogenesis and lipid metabolism changes in diabetic mice
migration of human aortic smooth muscle cells by inhibiting the and PA-induced HepG2 cells by regulating the HNF-4α-
activator protein-1 (AP-1) and NF-κB signaling pathways and modulated miR122 pathway (Wei S et al. (2016). Olanzapine
decreasing MMP-2/9 and urokinase-type plasminogen activator (OLZ), a second-generation antipsychotic drug, has adverse
(u-PA) expression (Liu et al., 2014). BBR (50 µmol/L) inhibited effects such as dyslipidemia and insulin resistance mediated by
chlamydia pneumoniae infection induced VSMC migration by the regulation of the AMP-activated protein kinase-α (AMPKα)-
downregulating MMP3 and MMP9 expression via PI3K (Ma sterol regulatory element binding protein (SREBP) pathway,
et al., 2015). Furthermore, BBR (10 µmol/L) ameliorated which also increases the risk of CVD. However, in an OLZ-
pulmonary arterial hypertension (PAH) and vascular remodeling induced adipogenesis model established in 3T3-L1 adipocytes, it
by inhibiting the thioredoxin (Trx)1/β-catenin pathway and was confirmed that BBR (5 µmol/L) may reverse the upregulation
inhibited hypoxia-induced pulmonary artery smooth muscle cells of SREBP and the downregulation of AMPKα phosphorylation to
proliferation, providing a new target toward the pathological prevent OLZ-induced lipid metabolism disorders (Li et al., 2016).
mechanism of PAH (Wande et al., 2020). More recent studies In clinical trials, a pre-mixed nutraceutical combination approved
have demonstrated that mechanical stretch promoted VSMC in Italy, consisting of 500 mg BBR, 200 mg red yeast rice and
proliferation and apoptosis by activating the protein disulfide 10 mg policosanols, showed a cholesterol-lowering effect. It
bond isomerase (PDI) redox system. BBR (100 µmol/L) inhibited significantly reduced TC and LDL-C levels in high cholesterol
the PDI-endoplasmic reticulum (ER) stress system and patients (Affuso et al., 2010) and in elderly patients with high
downregulated caspase-3 and caspase-12 expression, and thereby cholesterol who were intolerant to statins (Marazzi et al., 2011).
attenuate the concomitant increase in proliferation and apoptosis of In a parallel controlled study, a combination of BBR with
VSMC in response to mechanical stretch (Wang et al., 2020). policosanol, red yeast extract, folic acid and astaxanthin, and
As shown above, BBR shows treatment potential for AS and BBR alone were found to have similar efficacy and both could
arterial restenosis, and may indirectly prevent and treat AS reduce TC, TG and LDL-C levels to different degrees (Cicero
through certain signaling pathways closely related to AS, such et al., 2007). Some meta-analyses have also confirmed that BBR or
as MAPK, JNK, NF-κB, AMPK, ERK, AKT, PPARα-NO, AP-1, BBR-containing health products have beneficial effects on TC,
PI3K, Trx1/β-catenin, and PDI/MAPK/ERS. LDL-C and HDL regulation with good safety (Lan et al., 2015;
Wei X et al., 2016; Pirro et al., 2016), showing similar cholesterol-
lowering effects of statins (Weng et al., 2010). In a recent double-
HYPERLIPIDEMIA blind, randomized, placebo-controlled dose-ranging study, an
ionic salt berberine ursodeoxycholic acid (BUDCA) formed
The abnormal metabolism of blood lipids, including TC, TG, between BBR and ursodeoxycholic acid significantly reduced
LDL-C, and high-density lipoprotein cholesterol (HDL-C), is serum concentrations of TC and LDL-C, but not TG and
regarded as the main risk factor for the progression of AS and HDL-C concentrations, with the maximum dose of 2,000 mg/d

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Cai et al. Berberine Applications in Cardiovascular Diseases

at day 28. BUDCA shown to be well tolerated, and no significant chain (MLC). Increased Ca2+ influx causes intracellular Ca2+
adverse effects were reported even at doses of 2,000 mg/d (Di concentration to rise momentarily, which leads to MLC
Bisceglie et al., 2020). In summary, the lipid-lowering effect of phosphorylation and causes VSMC contraction (Ratz et al.,
BBR may be related to its regulating effects on PCSK9-LDLR, 2005). Transient receptor potential vanilloid 4 (TRPV4) is a
HNF-4α-miR122, and AMPKα-SREBP pathways. However, Ca2+ permeable cation channel (Ueda et al., 2011). It was
although BBR is proved to reduce the levels of TC, TG, and reported that BBR (100 mg/kg/d, p.o., 7 days) reduced blood
LDL-C, its effect on HDL has not been confirmed, and hence, pressure in deoxycorticosterone acetate-induced hypertensive
clinical administration of BBR as a lipid-lowering drug needs to mice and the dose of 50 mg/kg/d alleviated vascular stiffness
be further explored. in elderly Apo−/−E mice. Such results were possibly mediated by
the reduction of Ca2+ levels and CaM/MLC activity by BBR
through the inhibition of the TRPV4 channel, which caused
HYPERTENSION VSMC to relax and induced the anti-hypertensive as well as
anti-vascular aging effects (Wang et al., 2015a). The progression
As a chronic disease, hypertension is a major risk factor for of hypertension usually involves damage to the vascular
increased mortality in patients with CVD. The control of blood endothelial cells, accompanied by inflammation and apoptosis
pressure is related to the reduction of the occurrence of (Chung et al., 2004). The activation of myeloid differentiation
complications such as stroke, myocardial infarction, heart factor 88 (MyD88)-dependent toll-like receptor 4 (TLR4)
failure, AS, and ventricular arrhythmia (Ventura and Lavie, signaling pathway can promote the expression of interleukin-1
2019). A meta-analysis showed that in the treatment of receptor-associated kinase, nuclear factor-κB (NF-κB), and AP-1,
hypertension, lifestyle intervention combined with BBR and thus lead to the production of a large number of
reduces blood pressure better than lifestyle intervention or inflammatory factors, such as cyclooxygenase-2 (COX-2), IL-1
placebo alone, and BBR combined with oral antihypertensive and IL-6, which are associated with hypertension-induced
drug also reduced blood pressure better than the same endothelial damage. BBR (1.25, 2.5, and 5 µmol/L) could
antihypertensive drug. The usual intake of BBR was 0.6–2.7 g inhibit the apoptosis of aortic endothelial cells isolated from
per day. Additionally, it is noteworthy that no serious adverse SHR, decrease the expression of TLR4, MyD88, NF-κB, IL-6
effects were reported in 27 randomized controlled clinical trials and TNF-α, and have a certain protective effect on hypertension-
with BBR treatment alone (Lan et al., 2015). In a 2 years clinical induced vascular endothelial injury (Romero et al., 2011; Wang
study that analyzed biochemical markers of renal function and and Ding, 2015). CXC chemokine receptor 4 (CXCR4) plays a key
color Doppler ultrasound imaging, BBR showed a renal protective role in the mediation of EPCs for endothelial repair (Sainz and
effect for hypertensive patients with type-2 diabetes. In addition Sata, 2007). In a recent study, EPCs were isolated from
to baseline treatment, patients in the add-on group received oral prehypertensive patients, cultured, and transplanted into the
BBR for 24 months. The dose of BBR was 0.1 g three times per nude mice model of carotid artery injury. In the BBR (5 μmol/
day, with a 2 weeks no-treatment intervals every 5 months. The L) pretreated group, EPC significantly accelerated in vivo re-
associated mechanism may be the suppression of inflammation endothelialization and decreased the expression of CXCR4 and
and oxidative stress in patients with hypertension and diabetes, downstream Janus kinase-2 (JAK-2), indicating that BBR might
thereby improving renal hemodynamics and curtailing kidney protect endothelial cells by interfering with the CXCR4/JAK-2
injury (Dai et al., 2015). Nitric oxide (NO) can promote signaling pathway (Shao et al., 2018). ER stress is closely related to
vasodilation, prevent vasodilation disorders, and protect the the occurrence of hypertension and ROS is one of the major
vascular endothelium. In a recent clinical study, trimetazidine mediators (Schröder and Kaufman, 2005). BBR (1 μmol/L) may
combined with BBR was administered to coronary heart disease inhibit endothelium-dependent contractions by activating the
patients with comorbid essential hypertension for the first time. It AMPK pathway, thereby inhibiting ER stress, eliminating
was found that trimetazidine combined with BBR could ROS, and consequently downregulating COX-2expression in
significantly enhance the expression of endothelial NO carotid arteries of SHR, which shows a protective effect on
synthase gene (eNOS), increase the expression of NO, and vascular function (Liu et al., 2015). In short, BBR may reduce
improve flow-mediated dilation, indicating the improved blood pressure and prevent arteriosclerosis and endothelial
efficacy of combined drugs (Zhang et al., 2018). In a recent damage caused by hypertension by regulating the TRPV4,
animal experiment, BBR (50 mg/kg/d) was used as an MyD88-TLR4, CXCR4/JAK-2 and AMPK pathways.
intervention in spontaneously hypertensive rats (SHR). The
findings showed that blood pressure and circulating
endothelial microparticles level were partly reduced. In ISCHEMIC HEART DISEASE
addition, BBR maintained arterial elasticity by reducing aortic
pulse wave velocity and increasing the content of arterial media Ischemic heart disease (IHD) is a major contributor to the global
elastin fiber, indicating that endothelial function was improved by disease burden, and remains a substantial public health challenge
maintaining better endothelium-dependent vasodilation. (Zhang worldwide (Dai et al., 2020a; Virani et al., 2020). Myocardial
et al., 2020). The contraction of vascular smooth muscle cells infarction (MI) and ischemia-reperfusion injury (IR)-induced
(VSMC) is the main cause of vascular stiffness, mainly influenced myocardial cell death are the main cause of increased IHD
by the regulation of calmodulin (CaM)-dependent myosin light morbidity and mortality (Perricone and Heide, 2014). MI is

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Cai et al. Berberine Applications in Cardiovascular Diseases

the death of myocardial cells caused by local ischemia, while increasing the expression of angiogenesis-promoting factors
timely myocardial reperfusion through thrombolytic or PCI (Banaei et al., 2020). In summary, BBR may reduce apoptosis
restores blood flow in the occluded coronary artery. However, and improve myocardial I/R injury by regulating the expression
this process will inevitably cause further injury to myocardia and/or activity of the molecular factors including AMPK, miR-
(Hashmi and Al-Salam, 2015). Oxidative stress, Ca2+ overload, 29b, PI3K-Akt-eNOS, SIRT1, Notch1/Hes1-PTEN/Akt, AK2/
inflammatory response, and apoptosis are key factors in the STAT3, HIF-1a/BNIP3, and Smad7.
ischemic process (Hausenloy and Yellon, 2013; Perricone and
Heide, 2014). Results of many animal experiments have
confirmed that BBR has a protective effect on myocardial MYOCARDITIS AND CARDIOMYOPATHY
ischemia/reperfusion (MI/R) injury. In an experimental study,
after being pre-administrated into rat models of ischemia in vivo, Myocarditis is an inflammation of the myocardium caused by
BBR (100 mg/kg/d, i.g., 2 weeks) was found to significantly reduce infectious, idiopathic or autoimmune causes. A wide spectrum
the infarct area during IR injury, improve cardiac function, and of infectious pathogens including viruses, bacteria, and
reduce the concentration of AMPK, the ADP/ATP ratio and the chlamydia, as well as toxicity and hypersensitivity reactions
AMP/ATP ratio in myocardial ischemic areas. Therefore, BBR may cause cardiac damage and lead to inflammation. Viruses
may regulate AMPK activity in non-ischemic and ischemic areas (eg, enteroviruses such as coxsackievirus) are the most
of the heart (Chang et al., 2012). Despite the improvement of common infectious pathogens reported in acute
coronary ischemia after myocardial reperfusion, a large number myocarditis. Viral proliferation in cardiomyocytes can cause
of MI patients suffer from insufficient myocardial perfusion due tissue damage, and viral entry through its receptor activates
to impaired microvascular function. The induction of the immune signaling systems, which contributes to
angiogenesis can reduce the progression of myocardial cytoskeletal remodeling of host cells. In addition, ongoing
infarction and improve cardiac function (Van der Laan et al., inflammation results in changes in cardiac structure and the
2009). A recent study reported that BBR (100 μmol/L) can decline in function, which leads to the development of dilated
increase miR-29b expression, activate Akt in endothelial cells, cardiomyopathy (Sagar et al., 2012). Currently, coxsackievirus
and promote endothelial cell proliferation and migration, which B3 (CVB3)-induced acute myocarditis mice model is regarded
confirmed the importance of miR-29b in ischemic myocardial as the primary animal model for myocarditis, which shows
remodeling (Zhu et al., 2017). Diabetes increases the risk of many similarities to clinical myocarditis (Huber, 2016). A
ischemic heart disease. BBR (200 mg/kg/d, i.g., 12 weeks) recent study replicated CVB3 virus infection in human
improved cardiac functional recovery in diabetic rats subjected cervical carcinoma (HeLa) cells or primary cardiomyocyte
to I/R (Chen et al., 2014). It has also been reported that BBR models in vitro and demonstrated that BBR (100 μmol/L)
(200 mg/kg/d, i.g., 2 weeks) may reduce oxidative stress and inhibited the phosphorylation levels of JNK and p38 MAPK
myocardial inflammation by activating the silent information in cells, thereby inhibiting the replication of CVB3 in vitro (Dai
regulator 1 (SIRT1) signaling pathway (Yu et al., 2016), reduce ER et al., 2017). To explore the antiviral effects of BBR in vivo,
stress-induced apoptosis by activating the AK2/signal transducer mouse model of CVB3-induced myocarditis was established
and activator of transcription (STAT)3 signaling pathway (Zhao with intraperitoneal infection, and the results suggested that
et al., 2016), reduce cardiomyocyte apoptosis by improving BBR (100 mg/kg, i.g., 7 days) might reduce cardiac injury and
mitochondrial dysfunction (Wang et al., 2015b), and protected myocardial viral titer, and improve the survival rate and
the myocardial injury via the HIF-1a/BNIP3 pathway (Zhu et al., cardiac function as well. In addition, BBR treatment
2020) in MI/R injury rats. In vitro experiments revealed the inhibited macrophage infiltration and production of pro-
mechanism of the protective effect of BBR on MI/R injury might inflammatory cytokines/chemokines such as TNF-α, IL-6,
be it (50 μmol/L) inhibited apoptosis by activating the AMPK, IL-1β, CCL2, CCL5, and CXCL10 in mice of CVB3-induced
PI3K-Akt-eNOS, Smad7, and Notch1/Hes1-PTEN/Akt signaling myocarditis by inhibiting CVB3 replication. These results
pathways in cardiomyocytes (Chen et al., 2014; Yu et al., 2015; demonstrated the beneficial effects of BBR in alleviating
Yao et al., 2018). In addition, BBR (50 μmol/L) may protect CVB3-induced myocarditis in vivo (Dai et al., 2020b). Th17
myocytes by reducing the expression of caspase-3 (Yao et al., and Th1 are important immune cells involved in the
2018), inhibiting autophagy activation (Huang et al., 2015), pathogenesis of myocarditis, producing pathogenic
promoting mitochondrial autophagy, and promoting cytokines such as IL-17 and IFNg, respectively, which
cardiomyocyte proliferation (Zhu et al., 2020). When BBR facilitate the development of such autoimmune disease
(10 mg/kg/d, i.g., 5 days) extract was combined with high- (Tajiri et al., 2012). A recent study using purified porcine
intensity interval training (HIIT) in a rat model of myocardial cardiac myosin-induced experimental autoimmune
IR injury, the transcript levels of vascular endothelial cell growth myocarditis (EAM) model in Lewis rats indicated that BBR
factor, fibroblast growth factor-2, and platelet response factor-1 treatment (200 mg/kg/d, i.g., 3 weeks) inhibited Th17/Th1 cell
were significantly increased. In addition, caspase-3 protein level subpopulation differentiation, significantly reduced left
and infarct size were significantly reduced after 7 days of ventricular dysfunction and reversed disease progression in
reperfusion. It can be suggested that HIIT and BBR, alone or EAM rats. Moreover, BBR significantly inhibited the
in combination, might exert an effect on reducing myocardial overexpression of phosphorylated (p)-STAT1, STAT3 and
infarct size by reducing caspase-3 protein expression and STAT4. Thus, BBR could improve EAM by differentially

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Cai et al. Berberine Applications in Cardiovascular Diseases

regulating the activities of p-STAT1, p-STAT3 and p-STAT4, hypertrophy model of H9C2 cell. In addition, the hypertrophy
which further inhibited the differentiation of Th17 and Th1 of H9C2 cells was inhibited by upregulating the expression of
cells (Liu et al., 2016). Dilated cardiomyopathy is the most α-myosin heavy chain and downregulating the expression of
common form of cardiomyopathy induced by a variety of β-myosin heavy chain (Chang et al., 2015). In General, BBR
causes, ranging from myocarditis to alcohol and other may attenuate myocardial injury by regulating the activity of
toxins such as drugs, cardiotoxins and chemotherapeutic JNK-p38 MAPK, SIRT1-p66shc, AMPK-AKT, GSK3β,
agents, to rheumatic, endocrine and metabolic diseases, all STAT1, STAT3, STAT4, Sirt3, and other proteins.
of which can lead to reduced left ventricular systolic function
and left ventricular or biventricular dilatation (Hänselmann
et al., 2020). The anthracycline anticancer drug doxorubicin HEART FAILURE
(DOX) is an effective and commonly used chemotherapeutic
agent for the treatment of malignancies, and its main side Heart failure (HF) is the end stage of multiple heart diseases.
effect is cardiotoxicity. The main mechanisms are increased Ventricular remodeling is an important strategy for the
oxidative stress, down-regulation of gene expression and treatment of HF (Konstam et al., 2011). As early as 1988, a
induction of apoptosis (Chatterjee et al., 2010). Sirtuin 3 clinical study reported the protective effect of BBR on 12
(Sirt3) is the major mitochondrial deacetylase, and to date, patients with refractory congestive heart failure. The study
studies of Sirt3 have been limited to cell culture systems reported that intravenous infusion of BBR at a dose of
(Lombard et al., 2007). Sirt3 overexpression contributes to 0.2 mg/kg per minute could reduce the end-diastolic
the reduction of DOX cytotoxicity in H9c2 cardiomyocytes. In pressure of the right atrium and left ventricle, increase the
a pretreated H9c2 cell model, BBR (1 and 10 μmol/L) increased left ventricular ejection fraction, decrease the arteriovenous
Sirt3 protein levels in the presence of DOX and inhibited oxygen difference, and have a significant effect on
DOX-induced caspase 9 and 3-like activation (Coelho et al., hemodynamics (Marin-Neto et al., 1988). Moreover, oral
2017). In a recent study a rat model of DOX-induced administration of BBR is also proved effective for HF. A
cardiotoxicity was established. Compared with the DOX total of 156 patients with chronic heart failure (CHF) were
group, serum creatine kinase (CK), creatine kinase randomly divided into a treatment group and a placebo group.
isoenzyme (CK-MB) and MDA levels were decreased and In the treatment group, BBR at a dose of 1.2 g/d was orally
superoxide dismutase (SOD) and catalase (CAT) levels were administered in addition to conventional treatment.
increased in the BBR-treated group. BBR (10 mg/kg/d, i.g., Compared with the control group, the BBR group showed
10 days) attenuated mitochondrial Ca2+ overload, and restored an increase in the 6 min walking distance and left ventricular
the DOX-induced loss of mitochondrial membrane potential. ejection fraction, improvement of the dyspnea-fatigue index, a
BBR showed a protective effect against DOX-induced free decrease in the frequency and complexity of ventricular
radical damage in cardiac tissue, possibly by inhibiting premature contractions (VPCs), indicating that BBR might
intracellular Ca2+ elevation and attenuating mitochondrial improve quality of life and reduce VPCs and mortality in CHF
dysfunction (Xiong et al., 2018). Furthermore, a study, patients. (Zeng et al., 2003). In animal experiments, different
intervening in a DOX-induced cardiac injury rat model doses of BBR have been used to treat diastolic heart failure in
with BBR (20 mg/kg, i.g., 10 days) and in a DOX-induced rats, and could reduce the left ventricular end-diastolic
H9c2 cell injury model with 1 μmol/L BBR, demonstrated pressure and decrease the Ca2+ levels in myocardial cells in
BBR’s protective effect against DOX-induced cardiovascular a dose-dependent manner (Zhang et al., 2008). It has already
injury, which might be associated with upregulation of SIRT1 been reported that the advanced progression of pathologic
and downregulation of p66shc expression, resulting in myocardial hypertrophy can lead to pressure overload-
inhibition of ROS production, apoptosis and mitochondrial induced cardiac dysfunction or HF (Frey and Olson, 2003).
damage, thus improving cardiac dysfunction (Wu et al., 2019). Furthermore, the autophagic process that causes the
Diabetic cardiomyopathy (DCM) is a disease in which there is degradation of organelles and proteins is closely related to
abnormal myocardial structure and function in the absence of the pathogenesis of HF, which can remove the damaged
other cardiac risk factors (Jia et al., 2018). In a high-sucrose proteins and organelles, especially mitochondria and ER
and high-fat diet-fed and streptozotocin-induced rat model of (Nakai et al., 2007; Gottlieb and Mentzer, 2010). Studies
DCM, BBR (10, 30 mg/kg/d, i.g., 16 weeks) significantly have shown that by inhibiting the activity of the
improved cardiac diastolic and systolic function, as well as mammalian target of rapamycin (mTOR) and the
preventing cardiac hypertrophy. BBR intervention partially phosphorylation of its upstream extracellular signal-
reversed the metabolic disorders of biomarkers including regulated kinase (ERK1/2) and p38 mitogen-activated
phosphatidylcholine, phosphatidylethanolamine and protein kinase (MAPK), BBR (10 mg/kg/d, p.o., 4 weeks)
sphingolipids (Dong et al., 2018). BBR treatment could enhance autophagy and inhibit ER stress, thus
(100 mg/kg/d, i.g., 16 weeks) in diabetic rats partially playing an important role in preventing pressure overload-
improved cardiac function and attenuated the development induced myocardial hypertrophy and apoptosis (Li et al., 2014;
of cardiac fibrosis in rats with DCM, probably by increasing Hashemzaei et al., 2017; Chen et al., 2020). Additionally, BBR
cardiac AMPK and AKT activities and inhibiting glycogen also improved cardiac dysfunction and myocardial hypertrophy
synthase kinase-3 activity, as confirmed in a palmitate-induced by upregulating putative kinase 1 (PINK1)/cytosolic E3 ubiquitin

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Cai et al. Berberine Applications in Cardiovascular Diseases

ligase (Parkin)-mediated mitochondrial autophagy and inhibited the therapeutic potential of BBR (Feng et al., 2019). Furthermore,
cardiomyocyte apoptosis and mitochondrial damage BBR also has advantages in cancer, digestive and neurological
(Abudureyimu et al., 2020). It has also been reported that diseases therapy (Song et al., 2020). The present review
through the P21-activated kinase 1 (Pak1)-dependent signaling summarized the main pharmacological effects of BBR on
pathway, BBR (3 mg/kg/d) might suppress the upregulation of CVD and related mechanisms, including the up-to-date
Smad3-mediated muscle-specific F-box protein (Fbxo32) in work on myocarditis and cardiomyopathy, which provided
downstream promoter region and take part in the inhibition more reference for the future development of BBR drugs. In
of myocardial hypertrophy (Tsui et al., 2015). In brief, BBR may addition, the effects of BBR on protecting vascular
improve cardiac function and prevent heart failure by regulating endothelium, reducing the area of myocardial infarction
the mTOR pathway, the Pak1 pathway and Ca2+ concentration. and improving heart function undoubtedly confirm the
clinical prospects of BBR for improving long-term cardiac
prognosis. A recent review described that BBR exerts
SAFETY antioxidant, hepatoprotection, neuroprotection,
nephroprotection, pulmonary protection, as well as
In 2015, a meta-analysis including 27 RCTs on BBR reported immunomodulatory, antidiabetic and antitumor effects by
that no serious adverse effect was found during the treatment activating the nuclear factor erythroid 2 - related factor 2
of type 2 diabetes, hyperlipidemia, and hypertension and the (Nrf2) signaling pathway, which provides further insights into
treatments with BBR in such trials were at a relatively low cost the treatment of BBR for CVD although more studies are still
compared with other first-line medicines and treatments (Lan needed to demonstratae the modulatory effects of BBR
et al., 2015). However, human pharmacokinetic data show (Ashrafizadeh et al., 2020). In general, BBR is a promising
that BBR is poorly absorbed from the intestinal tract and option for CVD. The main formulation of BBR in clinical
rapidly metabolized in vivo, resulting in its low oral application is its hydrochloride or sulfate (Jin et al., 2016; Lin
bioavailability. Whereas, increasing gastrointestinal and Zhang, 2018), which have low oral bioavailability. Modern
reactions were found when treated with large dosages of oral formulations, BBR with different types of nanocarriers,
BBR, which is possibly a major obstacle to the application overcome this shortcoming (Mirhadi et al., 2018), and reduce
of BBR (Wang et al., 2017). With regard this, a transdermal the frequency of administration as much as possible, which not
formulation of BBR and the BBR precursor dihydroberberine only increases patient compliance, but also reduces potential
were developed (Buchanan et al., 2018). Transdermal side effects. However, since most of the mechanisms of actions
administration of BBR increased circulating levels of BBR are obtained from laboratory, it is necessary to get more
and avoided side effects on the gastrointestinal, kidney and conclusion from clinical trials to better evaluate the safety
liver. A nano-system BT1500M encapsulated with BBR in the and effectiveness of BBR, and to further clarify its mechanisms.
latest studies can increase gut absorption and intracellular
uptake of BBR which is thought to be promising in clinical
applications (Ma et al., 2020). AUTHOR CONTRIBUTIONS
YC and QX carried out the concepts and wrote the original draft.
SUMMARY AND OUTLOOK JL and YM participated the literature screening. KC proposed the
topic and polished the manuscript. WC and QL reviewed and
Previous experimental and clinical studies of BBR in the proofread the manuscript.
treatment of CVD were relatively comprehensively reviewed
which indicated the therapeutic effects of BBR on various
CVD, including arrhythmia, atherosclerosis, hyperlipidemia, FUNDING
hypertension, ischemic heart disease, myocarditis and
cardiomyopathy and heart failure. Such effects are mediated This work was supported by the National Natural Science
via multiple targets, including pathway targets such as MAPK, Foundation of China (grant number 81874458) and the
JNK, NF-κB, AMPK, ERK, AKT, TRPV4, MyD88-TLR4, and so Authorized Project of China Academy of Chinese Medical
on (Figure 2, Table 1). A recent review summarizes the Sciences (ZZ13–036–4).
pharmacological properties and therapeutic applications of
BBR in CVD and metabolic diseases, including cardiac
hypertrophy, HF, AS, IR, stroke, arrhythmia, DM, and non- ACKNOWLEDGMENTS
alcoholic fatty liver disease, through 2019. It provided multiple
perspectives on the efficacies and mechanisms of BBR All the authors critically reviewed the literature and contributed
interventions in a wide range of diseases, giving a glimpse of to drafting the manuscript.

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Cai et al. Berberine Applications in Cardiovascular Diseases

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Zheng, H., Zhu, F., Miao, P., Mao, Z., Redfearn, D. P., and Cao, R. Y. (2017). in vivo by regulating the mitophagy-mediated HIF-1α/BNIP3 pathway.
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Zhou, Z. W., Zheng, H. C., Zhao, L. F., Li, W., Hou, J. W., Yu, Y., et al. (2015). Effect Conflict of Interest: The authors declare that the research was conducted in the
of berberine on acetylcholine-induced atrial fibrillation in rabbit. Am. J. Transl. absence of any commercial or financial relationships that could be construed as a
Res. 7, 1450–1457. potential conflict of interest.
Zhu, M. L., Yin, Y. L., Ping, S., Yu, H. Y., Wan, G. R., Jian, X., et al. (2017). Berberine
promotes ischemia-induced angiogenesis in mice heart via upregulation of Copyright © 2021 Cai, Xin, Lu, Miao, Lin, Cong and Chen. This is an open-access
microRNA-29b. Clin. Exp. Hypertens. 39, 672–679. doi:10.1080/10641963.2017. article distributed under the terms of the Creative Commons Attribution License (CC
1313853 BY). The use, distribution or reproduction in other forums is permitted, provided the
Zhu, N., Li, J., Li, Y., Zhang, Y., Du, Q., and Hao, P. (2020). Berberine protects original author(s) and the copyright owner(s) are credited and that the original
against simulated ischemia/reperfusion injury-induced H9C2 cardiomyocytes publication in this journal is cited, in accordance with accepted academic practice. No
apoptosis in vitro and myocardial ischemia/reperfusion-induced apoptosis use, distribution or reproduction is permitted which does not comply with these terms.

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Cai et al. Berberine Applications in Cardiovascular Diseases

GLOSSARY MDA malondialdehyde

MI myocardial infarction
AF atrial fibrillation MI/R myocardial ischemia/reperfusion
AMPK AMP-activated protein kinase MLC myosin light chain
AP-1 activator protein-1 MMP matrix metalloproteinase
Apo−/−E apolipoprotein E gene knockout mTOR mammalian target of rapamycin
AS atherosclerosis MyD88 myeloid differentiation factor 88
BBR berberine NF-κB nuclear factor-κB
CaM calmodulin NH neointimal hyperplasia
CHF chronic heart failure NO nitric oxide
COX-2 cyclooxygenase-2 OLZ olanzapine
CVB3 coxsackievirus B3 ox-LDL oxidized low-density lipoprotein
CVD cardiovascular diseases PA palmitate
CXCR4 CXC chemokine receptor 4
PAH pulmonary arterial hypertension
DCM diabetic cardiomyopathy
Pak1 p21-activated kinase 1
DOX doxorubicin
PCI percutaneous coronary intervention
EAM experimental autoimmune myocarditis
ECM extracellular matrix PCSK9 proprotein convertase subtilisin/kexin9 type
EMMPRIN extracellular matrix metalloproteinase inducer PDI protein disulfide bond isomerase
ERK extracellular signal-regulated kinases PINK1 putative kinase 1
ERS endoplasmic reticulum stress ROS reactive oxygen species
HF heart failure SHR spontaneously hypertensive rats
HDL-C high-density lipoprotein cholesterol SIRT1 silent information regulator 1
HIIT high-intensity interval training Sirt3 sirtuin 3
HNF-4α hepatocyte nuclear factor 4α SREBP sterol regulatory element binding protein
HUVECs human umbilical vein endothelial cells STAT signal transducer and activator of transcription
IHD ischemic heart disease TC total cholesterol
IL interleukin TG triglyceride
IR ischemia-reperfusion TLR4 toll-like receptor 4
JAK-2 janus kinase-2 TNF-α tumor necrosis factor α
JNK jun n- terminal kinases TRPV4 transient receptor potential vanilloid 4
LDL-C low density lipoprotein cholesterol Trx thioredoxin
LDLR LDL receptor u-PA urokinase-type plasminogen activator
LOX1 lipoprotein receptor-1 VPCs ventricular premature contractions
LPS endotoxin VSMC vascular smooth muscle cells
MAPK mitogen-activated protein kinase VT ventricular tachycardia

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