ASIA-PACIFIC JOURNAL OF CARDIOLOGY REVIEW ARTICLE

Role of ABC Transporters in Cardiovascular Diseases

João Marcos A Delou1, Anibal G Lopes2 and Márcia AM Capella1,2
Affiliations: 1Instituto de Bioquı́mica Médica and 2Instituto de Biofı́sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

A B S T R A C T

Hypertension and atherosclerosis represent major causes of cardiovascular events. Both are chronic inflammatory disorders associated
with an increased risk of mortality and morbidity. In the last few years, increasing evidence points to the involvement of ABC transporters in
inflammation, hypertension, and atherosclerosis. The main ABC proteins related to these diseases are ABCA1, ABCB1, ABCC1, ABCG2, and
possibly ABCG5 and ABCG8. Recent studies have suggested a direct participation of both ABCB1 and ABCC1 in the genesis of hypertension,
by modulating plasma aldosterone disposition and tissue uptake or by modulating the hypertensive response to angiotensin II respectively.
Moreover, some ABC transporters are known to transport several drugs to urine, including some antihypertensive drugs. This review
presents a concise explanation about each member of the ABC protein superfamily and summarizes the recent findings regarding the
relationship between these proteins and the inflammatory disorders that lead to cardiovascular events.

Keywords: ABCA1, ABCB1, ABCC1, ABCG2, hypertension, atherosclerosis

Correspondence: João Marcos A Delou, Instituto de Biofı́sica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS—Bloco G,
21949-900—Rio de Janeiro, RJ, Brazil. Fax: +55-(21)2280-8193; e-mail: jmdelou@gmail.com

INTRODUCTION SEARCH STRATEGY AND SELECTION CRITERIA

Cardiovascular diseases are the main cause of death
worldwide. Hypertension and atherosclerosis are both
chronic inflammatory disorders associated with an increased
risk of mortality and morbidity, and represent major causes of
cardiovascular events, such as stroke, ischemia, and infarc-
tion. Hypertension is estimated to cause 4.5% of current
global disease burden, and its prevalence is similar in both
developing and developed countries [1]. According to a recent
review, approximately 54% of stroke, 47% of ischemic heart
disease, and 25% of other cardiovascular diseases worldwide
can be attributable to high blood pressure [2].
In the last few years, increasing evidence has pointed to the
involvement of ABC proteins in hypertension, atherosclerosis,
and cardiovascular events. For example, ABCB1 and ABCC1,
the two main ABC proteins first described in multidrug-
resistant (MDR) tumors, are known to physiologically
transport several endobiotics, including hormones, and have
recently been associated with hypertension [3, 4]. In addition,
ABCB1 and ABCG2 are known to secrete a number of drugs to
urine, including some antihypertensives [5, 6], and several
ABC transporters are lipid transporters and seem to
contribute to the development of atherosclerosis.
OBJECTIVES
The aim of this review is to identify and summarize the
recent findings about ABC proteins that might be involved in
the genesis and/or maintenance of mainly hypertension, but
also atherosclerosis, and therefore related to the global
burden of cardiovascular diseases.
Data for this review were identified by searching Pubmed,
and references from relevant articles using the search terms
‘‘ABCA and atherosclerosis’’, ‘‘ABCA1 and atherosclerosis’’,
‘‘ABCA and hypertension’’, ‘‘ABCB and hypertension’’,
‘‘ABCC and hypertension’’, ‘‘ABCD and hypertension’’,
‘‘ABCE and hypertension’’, ‘‘ABCF and hypertension’’ and
‘‘ABCG and hypertension’’, ‘‘P-glycoprotein and hyperten-
sion’’, ‘‘MDR1 and hypertension’’, ‘‘MRP1 and hypertension’’,
‘‘BCRP and hypertension’’, ‘‘ABCA1 and hypertension’’,
‘‘ABCG2 and hypertension’’ were used. Papers published in
English from 1980 to August 1, 2009 were included.
THE ABC SUPERFAMILY
The ATP binding cassette (ABC) superfamily is one of the
largest families of proteins known, consisting of more than
3000 members with representatives from every kingdom of
life. This superfamily comprises two types of proteins, the
ABC transporters and the cytosolic ABC-ATPases. The
majority of the ABC proteins are transmembrane transporters
that actively translocate a wide range of substrates among
cellular compartments using adenosine triphosphate (ATP)
hydrolysis, whereas the cytosolic ABC-ATPases are a smaller
group involved in the maintenance and repair of chromo-
somes and in protein synthesis. For further information, a
good review on the subject was published recently [7].
The human ABC transporters
The human ABC transporters are integral membrane
transporter proteins related to several cellular functions.

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There are approximately 50 known human ABC transporters,
subdivided into seven subfamilies with names ranging from A
to G, always after the ABC letters: ABCA, ABCB, ABCC,
ABCD, ABCE, ABCF, and ABCG. Each protein in these
subfamilies is identified by a number positioned after the four
letters that designate the subfamily, e.g., ABCC1, ABCG2. To
be classified as an ABC transporter, the protein must share
some common characteristics; for instance, it must present at
least one cytoplasmic nucleotide binding domain (NBD),
which is the ATP catalytic site, and must present at least one
extracellular transmembrane domain (TM), which is not
present in the cytosolic ABC-ATPases, although other
extracellular and intracellular domains are common and very
variable among transporters (Figure 1).
The human ABC transporters are active transmembrane
proteins that use the cleavage of ATP to ADP+Pi in order to
transport substances across the membrane, usually against a
concentration gradient. Although there are both importers
and exporters in the ABC superfamily, no importer has been
described in human cells so far; for this reason, in humans,
they are commonly referred to as efflux pumps [7, 8]. The
substrates recognized by these transporters are numerous,
such as hormones, lipids, peptides, toxins, drugs, plant
metabolites, and others. Some substrates of two ABC
transporters are presented in Table 1 [9–11]. In the last few
years, some of these proteins have been associated with
cardiovascular diseases.
ABCA SUBFAMILY
The ABCA subfamily is composed of at least 13 members
mostly consisting of cholesterol and lipid transporters [7].
ABCA1 is the most studied protein in this family. It is
constitutively expressed in several tissues and has recently
been associated with atherosclerosis. ABCA1 is a cholesterol
Figure 1. Schematic model of ABC transporters. The predicted structures of ABCA1, ABCB1, ABCC1, and ABCG2 are represented as members of each family of
ABC transporters. The five- or six-helix transmembrane domains, the ATP active sites (NBD), the intracellular and extracellular loops, and the glycosylations are
indicated.
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exporter and a suggested apolipoprotein receptor, recently
recognized as a major regulator of cellular cholesterol and
phospholipid homeostasis (Figure 2). Until now, it is the
only ABC protein with a receptor-like signaling pathway, via
Janis kinase 2 [12, 13], protein kinase C [14], Cdc42, and
other protein kinases [15]. Mutations in the ABCA1 gene have
been associated with Tangier disease, which features
physiological deficiencies in high-density lipoprotein (HDL)
and apolipoprotein E [16–18].
Association of polymorphisms of ABCA1 and ROS1 with
hypertension in Japanese individuals has been reported [19],
and it has been shown that ABCA1 expression is decreased in
untreated hypertensive patients and normalized in patients
receiving antihypertensive treatment [20].
Mutations in ABCA1 predicted risk of ischemic heart disease
in the Copenhagen City Heart Study Population [21], but
lower plasma levels of HDL cholesterol due to heterozygosity
for loss-of-function mutations in ABCA1 were not associated
with an increased risk of ischemic heart disease [22].
An increased frequency of ABCA1 polymorphism was
observed in a sample of coronary artery disease cases in
recent genome-wide association scans (GWAS) [23].
Moreover, two polymorphisms in the promoter region (the
–565C/T and the –191G/C variants) were inversely associated
with risk of coronary heart disease among healthy women,
without pronounced effects on plasma lipids [24]. It was also
shown that the G1051A polymorphism (a G to A substitution
at position 1051 in exon 7, resulting in a change from an
arginine to a lysine at residue 219) was associated with a
decreased risk of coronary artery disease in some European
and American populations [25–29], but not in two Japanese
studies [30, 31]. This polymorphism was previously asso-
ciated with slightly higher HDL cholesterol and lower
prevalence of coronary artery calcification in another study
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Table 1. ABCB1 and ABCG2 Substrates: Examples of Endogenous and Exogenous Substances transported by ABC Proteins arranged in Classes

Substrates of ABCB19 Substrates of ABCG210,11

Anti-HIV Anti-HIV
Aprenavir, Atazanavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Abacavir, Nelfinavir, Zidovudine
Ritonavir, Saquinavir, Tipranavir

Antibiotics Antibiotics
Grepafloxacin, Erythromycin, Rifampicin Ciprofloxacin, Nitrofurantoin, Norfloxacin, Ofloxacin, Sulfasalazine
Anticancer Drugs Anticancer Drugs
Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, 9-aminocamptothecin, Bisantrene, Karenitecin (BNP1350), Chlorin E6, CL1033,
Etoposide, Cisplatin, Paclitaxel, Docetaxel, Teniposide, Cytarabine, Cladribine, Daunorubicin, Diflomotecan (BN-80915), Doxorubicin, Exatecan
Fluorouracil, Methotrexate, Mitomycin, Vindestine Mesylate (DX-8951f), Edevarone (metabolites), Epirubicin, Erlotinib,
Etoposide, Flavopiridol, Gefitinib, Gimatecan, GW1843, Heterocyclic amines,
Homocamptothecin, Imatinib, J-107088, JNJ-7706621, Methotrexate,
Mitoxantrone, NB0506, SN-38 (Irinotecan metabolite), Teniposide,
Tomudex, Topotecan, UCN-01,
Antihistamines Antihistamines
Terfenadine, Domperidone Cimetidine
Cardiac Drugs Phytoestrogens
Digoxin, Quinidine, Lovastatin, Celiprolol, Diltiazem, Talinolol, Resveratrol, Quercetin, Daidzein, Coumestrol, Genistein
Verapamil

Antifungals Antihypertensive
Itraconazole, Sparfloxacin Olmesartan
CNS Drugs Antiplatelet
Levomeprazine, Protriptylene, Ripseridone Dipyridamole
Hormones Antirheumatic
Aldosterone, Estradiol, Hydrocortisone Leflunomide

Steroid Statins
Dexamethasone Pitavastatin, Posuvastatin
Anxiolytics, sedatives Antidiabetic
Amitriptyline, Midazolam, Nefazodone Glyburide
Immunosupressive Agents Vitamins and cofactors
Cyclosporine A, FK506, Methylprednisolone, Prednisolone, Tacrolimus Riboflavin (B2), Flavin mononucleotide (FMN), Biotin (B7), Menadione (K3),
Triglutamate
Opiates Porphyrins

Fentanyl, Loperamide, Methadone, Morphine Pheophorbide A, Pyropheophorbide A

Antiemetic
Ondansetron

[32], and it was shown recently that it is associated with a
5.5% higher concentration of small HDL particles [33],
suggesting that this allele may protect against subclinical
cardiovascular disease. On the other hand, it was observed
that the T allele of the 2565 C/T polymorphism may increase
risk for subclinical cardiovascular disease [32]. A recent
review was published concerning polymorphisms in the
ABCA1 gene, HDL cholesterol, and risk of ischemic heart
disease in the general population [22].
ABCA1 is one of the major modulators of macrophage foam
cell formation and atherosclerotic lesions [20, 34, 35].
Transcriptional repression of the ABCA1 gene in macrophages
by the activation of angiotensin II receptor type 1 (a well-known
receptor that mediates the classic pressor effects of angiotensin
II but also the proinflammatory, proliferative, and pro-
oxidative properties commonly increased in hypertension)
alters macrophage cholesterol homeostasis and promotes
foam cell formation and atherosclerosis [36]. Last year, two
polymorphisms in the ABCA1 gene were investigated, and it was
suggested that they could facilitate myocardial infarction in the
Japanese population; however, the correlation was not
significant [19].
Cyclosporine A (CSA) stimulates the renal epithelial sodium
channel by elevating cholesterol content in the membrane in

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Figure 2. ABCA1 and ABCG1 involvement in cholesterol homeostasis. ABCA1 promotes the transfer of phospholipids to lipid-poor forms of apolipoprotein
(APOA1), the major protein component of HDLs, forming the nascent HDL. The mechanisms for this transfer are not fully understood, but ABCA1 apparently
binds to APOA1, eliciting the translocation of phospholipids and cholesterol across the plasma membrane bilayer. Other enzymes (not shown here) participate
in the process, which leads to mature HDL particles, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL). ABCG1 promotes the efflux of
cholesterol to mature HDL particles. Hyperactivity of ABCA1 and/or ABCG1 might contribute to excessive cholesterol plasma concentrations, facilitating the
development of atherosclerosis. Other ABC transporters might contribute to the establishment of atherosclerosis by other pathways, as proinflammatory
mediator secretion by ABCC1 or ABCG2. The schematic cell might represent a macrophage, which expresses all four proteins, but also other cells, not
necessarily expressing all proteins.

an ABCA1-mediated mechanism. Also, CsA significantly
increased epithelial sodium channel (ENaC) open probability.
As enhanced ENaC activity is known to cause hypertension,
these data together suggest that CsA may cause hypertension
by stimulating ENaC through a pathway associated with
inhibition of ABCA1 and the consequent elevation of
cholesterol in the cells [37].
ABCB SUBFAMILY
The ABCB subfamily is one of the most studied families and
is composed of at least 11 members with two TM and two
NBD [7]. The first publication concerning the involvement of
an ABCB protein in hypertension was our study showing that
a high-sodium diet diminished ABCB1 expression in rats [38].
We also showed, in a more recent study, that ABCB1, but not
ABCC1, is downregulated in peripheral blood mononuclear
cells and in the kidneys of spontaneously hypertensive rats
[39]. Our results were further confirmed by another group
that also observed a reduced expression of the abcb1a and
abcb1b genes in the rat liver and kidney, but an increased
expression of these genes in the duodenum, jejunum, and
ileum, suggesting that the regulation of this protein is tissue
specific [40]. Confirming this hypothesis, it has been shown
that the expression of abcb1a mRNA was induced in the
murine small intestine, but not in the kidney, by treatment
with the pharnesoid X receptor activators rifampicin and St
John’s wort [41]. Indeed, the expression of ABC transporters
can be regulated by several other hormones with either
membrane or nuclear receptors, such as insulin [42],
estrogen [43], and progesterone [43, 44]. For example,
pregnane X receptor and constitutive androstane receptor
have been reported to alter the expression of ABCB1, ABCC2,
ABCC3, and ABCG2 [45]. ABCB1 expression is also induced
by thyroid receptor in a pregnane X receptor-independent
fashion [46, 47].
We also showed that the mRNA expression of ABCB1 was
diminished in adrenalectomized rats, suggesting that aldoster-
one could be an endogenous regulator of this protein [39].
More recently, it was shown that aldosterone activity in the
plasma, brain, and heart was significantly higher in ABCB1-
deficient mice [48]. These data point to a possible role for
ABCB1 in hypertension and were followed by additional studies
in humans. Because aldosterone plays an important role in the
pathophysiology of numerous cardiovascular disorders,
including hypertension, the regulation of its plasma disposi-
tion and tissue uptake is essential for the maintenance of blood
pressure. It is known that human ABCB1 transports aldoster-
one [5, 49]. Therefore, studies relating ABCB1 expression and
its polymorphisms with plasma disposition and tissue uptake
of aldosterone were carried out.
A recent study showed that the combined action of ABCB1 and
CYP3A5 gene polymorphisms was associated with postproximal
tubular sodium reabsorption, plasma renin activity, plasma
aldosterone, and an altered blood pressure response to the
angiotensin-converting enzyme inhibitor lisinopril [50]. This
same group detected that some ABCB1 gene polymorphisms
were related to altered glomerular filtration rate in Caucasians,
whereas other polymorphisms of this gene were associated with

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renal function and hemodynamics in Africans, suggesting that
the ABCB1 gene is related to renal function in the general
population [51]. This year, it was reported that, among patients
with essential hypertension, polymorphisms in the ABCB1 gene
that influence its expression, alter the transport of many drugs,
and modulate digoxin kinetics are related to circulating
endogenous ouabain (a pressor hormone) and increased
diastolic blood pressure, most likely by influencing the synthesis
and transmembrane transport of ouabain respectively [52].
Therefore, the results obtained by several authors, performed in
either animals or humans, strongly suggest that ABCB1
contributes to blood pressure regulation, possibly via the
renin–angiotensin–aldosterone system, through the regulation
of plasma levels and tissue uptake of aldosterone and ouabain.
Besides its role in the plasma disposition of hormones
related to hypertension, it was shown that murine myocardial
and hepatic Abcb1a mRNA expression was significantly
increased after 2 weeks of induced intermittent hypoxia
[53]. This is not a surprising result, as it is already known
that hypoxia is a strong stimulus for ABCB1 expression, as
well as inflammation and hyperthermia. Another role for this
protein is the secretion of several drugs, including anti-
hypertensives, to urine. For instance, losartan was shown to
be a substrate for ABCB1, and its binding and transport were
not altered by the common variation C3435T in the ABCB1
gene [54]. Moreover, the commercial antiplatelet dipyrida-
mole was identified as an ABCB1 modulator, strong enough
to reverse ABCB1-mediated multidrug resistance (MDR) in
melanoma cells in vitro and in vivo, including an increase in
intratumoral concentrations of doxorubicin without affecting
C57BL/6 pharmacokinetics [55]. It acts via inhibition of
adenosine uptake into platelets, erythrocytes, and endothelial
cells, increasing the circulating concentration of adenosine
and activating the adenosine receptor 2.
In view of the results summarized above, it is clear that
more studies are needed to fully understand the several
apparent roles of ABCB1 protein in hypertension.
ABCC SUBFAMILY
The ABCC subfamily is composed of at least 13 members with
three TM and two NBD [7]. Studies performed in knockout mice
suggest that its first member, the ABCC1 protein, has a major
role in blood pressure regulation, although there has been no
study relating ABCC1 genetic variants with blood pressure or
hypertension in humans up to now.
This protein transports a wide variety of neutral and
hydrophobic compounds and also several glutathione,
glucuronide, and sulfate conjugates [56]. Owing to its
versatility and ubiquitous tissue distribution, ABCC1 is
involved in various physiological functions, such as defense
against xenobiotics and endogenous toxic metabolites,
leukotriene-mediated inflammatory responses, and protection
against oxidative stress [54–59].
It is known that the production of reactive oxygen species is
increased in hypertension and in oscillatory shear stress,
which occurs at points in the circulation predisposed to
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ABC transporters in cardiovascular diseases
atherosclerosis. Human endothelial cells express ABCC1, and
this protein exports oxidized glutathione out of these cells. It
has been shown that oscillatory shear stress caused a strong
export of oxidized glutathione, which was prevented by the
ABCC1 inhibitor MK571 and by ABCC1 small interfering RNA
[60]. According to the authors, the inhibition of ABCC1
prevented the decline in intracellular reduced glutathione,
preserved the intracellular reduced glutathione Nernst poten-
tial, and reduced apoptosis caused by oscillatory shear.
Moreover, the altered endothelium-dependent vasodilatation
caused by hypertension was ameliorated in ABCC1 knockout
mice.
This same group showed that angiotensin II-induced hyper-
tension increased oxidized glutathione export and decreased the
vascular levels of reduced glutathione in wild-type but not in
ABCC12/2 mice [61]. The authors showed that the aortic
endothelium-dependent vasodilatation was reduced in wild-type
mice but was unchanged in ABCC12/2 mice after angiotensin II
infusion. Moreover, superoxide production, expression of
several NADPH oxidase subunits, and the levels of nitric oxide
(NO) were greatly altered only in wild-type mice. They also
showed that the hypertension caused by angiotensin II was
markedly blunted in ABCC12/2 mice, strongly suggesting that
ABCC1 activity is essential for the hypertensive response to
angiotensin II. In a more recent study, the same authors showed
that angiotensin II triggers the release of leukotriene C4 (a
proinflammatory eicosanoid) in vascular smooth muscle cells
via ABCC1 [62], suggesting that this protein might be a new
target for the therapeutic handling of hypertension.
In addition, it was shown that treatment with the ABCC1
inhibitor MK571 reduced vascular reactive oxygen species
production, significantly improved endothelial function, and
ameliorated atherosclerotic plaque generation in athero-
sclerosis-prone, apolipoprotein -deficient mice on a high-
cholesterol diet, suggesting that ABCC1 is also a potentially
promising target for atheroprotective therapy [60].
ABCD, ABCE, AND ABCF SUBFAMILY
The ABCD subfamily is composed of at least four members
with one TM and one NBD. They are all functional homo- or
heterodimeric transporters related to the peroxisomal trans-
port of fatty acyl-CoA.
The ABCE and the ABCF subfamily comprise the families of
cytosolic ABC-ATPases with at least one and four members
respectively. They present two NBD, but lack the TM. Very
little is known about them [7]. ABCE1 is an RNase L
inhibitor, therefore permissive for protein synthesis [63].
ABCF1 is a phosphoprotein that interacts with the eukaryotic
initiation factor 2, phosphorylated at two sites by CK2,
enhancing protein synthesis [64]. No obvious correlation
among these facts and any cardiovascular-related disease have
been suggested until now.
ABCG SUBFAMILY
The ABCG subfamily is composed of at least six members
with one TM and one NBD [7].
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In 2008, a study with Abca12/2, Abcg12/2, and Abca12/
2
Abcg12/2 mice showed that Abcg1 expression in endothelial
cells contributes greatly to endothelial nitric oxide synthase
(eNOS) maintenance in its active dimeric form and, conse-
quently, to adequate endothelial-induced vasorelaxation. Both
Abcg12/2 and Abca12/2Abcg12/2 mice fed with a high-
cholesterol diet accumulated diet oxysterols in endothelial
cells and had increased atherosclerosis [65].
ABCG2 expression is modulated by a functional steroid-
binding element present in its promoter [66] and by
progesterone receptors A and B [67]. In humans, it has been
shown that ABCA1 and ABCG1 expression is decreased in
untreated hypertensive patients, and their expression is normal-
ized in patients receiving antihypertensive treatment [20].
In a recent cardiovascular health study, it was found that a
single nucleotide polymorphism of ABCG2 (Val12Met) was
associated with increased risk of ischemic stroke in both white
and black participants [68]. Homozygotes of the Val allele of
ABCG2 were at higher risk of stroke than carriers of the Met
allele. This gene variant had previously been associated with
angiographically defined severe coronary artery disease in two
case–control studies [69]. Interestingly, it has been shown that
the Met variant of ABCG2 has a lower transport activity and
altered pattern of localization when compared with the Val
variant [70]. Therefore, it seems that the Met variant of the
ABCG2 protein has a protective function in the vascular
endothelium. In addition, it has been shown that ABCG2 is
involved in body regulation of menadione (vitamin K3), which
is necessary for the production of prothrombin and other blood
clotting factors in humans [71].
As with hypertension, the incidence of stroke is increasing in
people living in both developed and developing countries, and
it is well established that age and hypertension are the most
powerful risk factors for stroke [72, 73]. As discussed above,
evidence obtained recently in two studies is consistent with a
correlation between the ABCG2 polymorphisms and the
leading causes of morbidity and mortality in hypertensive
patients, namely stroke and coronary artery disease. Because
there is no study relating a direct role for ABCG2 in the genesis
of hypertension, more studies relating ABCG2 with stroke and
coronary artery disease and its role in vitamin K regulation are
necessary in order to better understand this association.
Sitosterolemia, or phytosterolemia, is most prominently
characterized by hyperabsorption and impaired biliary elim-
ination of dietary plant sterols. It is a recessive disorder in
which patients retain 15–20% of dietary plant sterols, whereas
normal individuals absorb less than 1–5%, and it has been
attributed to mutations in either the ABCG5 or the ABCG8
genes [71, 74]. In humans, associations between both D19H
and T400K polymorphisms in the ABCG8 gene and increased
atherosclerosis were recently identified in a large cohort study
of 2012 patients with heterozygous familial hypercholester-
olemia [75].
Sitosterolemic patients develop premature atherosclerosis
[76], xanthomas, and premature coronary heart disease as a
result of sterol deposition in the skin, tendons, and coronary
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arteries [77, 78]. Decreased expression of both intestinal
Abcg5 and Abcg8 has also been proposed to explain the
increased systolic blood pressure, the earlier onset of stroke,
and the decreased lifespan of salt-loaded, stroke-prone,
spontaneously hypertensive rats (SHRSP) treated with a
phytosterol-rich diet [79]. A missense mutation in Abcg5
confers sitosterolemia in both SHRSP and their control
Wistar–Kyoto (WKY) rats [80], although this mutation does
not segregate with hypertension [81].
ROLE OF ABC TRANSPORTERS IN DRUG
UPTAKE AND DISPOSITION
Besides their roles in the genesis and maintenance of
hypertension and atherosclerosis, several pharmacokinetic
studies have demonstrated the importance of some ABC
transporters in limiting oral drug uptake and disposition,
including several antihypertensive drugs, to target organs. It
has been proposed that interindividual variability in drug
response and adverse drug reactions are related to alterations
in the ABC membrane transporters, affecting chemosensitiv-
ity and drug resistance.
The reasons for altered expression and/or activity of such
transporters vary from gene polymorphisms to modulation by
endogenous substances. For example, ABCB1 and ABCG2 are
differently modulated by proinflammatory cytokines. ABCG2
mRNA levels were significantly reduced by interleukin (IL)-1b,
IL-6, and tumor necrosis factor (TNF)-a. These cytokines also
significantly reduced the ABCG2 activity as assessed by
mitoxantrone uptake experiments. ABCB1 mRNA levels were
slightly reduced by IL-6, but significantly increased after TNF-
a treatment. TNF-a also increased protein expression of
ABCB1, but the uptake of its substrate rhodamine 123 was not
affected by any of the cytokines [82].
On the other hand, nitrolinoleic acid, an electrophilic
derivative of linoleic acid that has anti-inflammatory,
antiplatelet, and vasodilator properties, was identified as a
glutathione-dependent substrate of ABCC1, which might also
suggest it as a glutathione-dependent substrate of other
ABCCs and/or also ABCG2 [83].
Although in the last few years, several studies have focused
on the contribution of genetic polymorphisms of transport
proteins to interindividual variability in the efficacy and safety
of cancer therapy [84, 85], little is known about the influence
of such proteins and their polymorphisms for the effective-
ness of antihypertensive therapy. It has been shown that the
expression of ABCB1 in the intestine was increased by the
aldosterone antagonist spironolactone [86], widely used in
the treatment of patients with congestive heart failure. This
increased expression led to a diminished absorption of
digoxin, which is transported by ABCB1 in the intestine and
liver [87]. On the other hand, verapamil, an inhibitor of both
ABCB1 [88] and ABCC1 [89], was shown to increase plasma
digoxin concentration, a possible consequence of a decreased
renal tubular elimination of digoxin [90]. Also, the toxicity of
the interaction between quinidine and digoxin was shown to
be attributed to the inhibition of ABCB1 [91].
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In contrast, carvedilol, a b-adrenoceptor antagonist with
vasodilating activity used for the treatment of hypertension
and coronary artery disease [92], was shown to reverse
ABCB1-mediated MDR to anticancer drugs in tumor cells in
vitro [93]. This effect is not common to all b-adrenoceptor
antagonists, as the b1-adrenoceptor selective antagonists
propranolol, metoprolol, and atenolol did not affect ABCB1-
mediated MDR [94], suggesting that this effect of carvedilol
was independent of its action on b-adrenoceptors. However,
it has been shown that talinolol (a b1-adrenoceptor selective
antagonist) inhibits the ABCB1-mediated transport of digoxin
[95] and that celiprolol (a b1-adrenoceptor selective antago-
nist with slight a2-agonist action) and acebutolol (a b1-
adrenoceptor selective antagonist) are substrates for ABCB1
[96–98]. This interaction was confirmed in patients receiving
cyclosporine treatment after cardiac transplants in combina-
tion with carvedilol, but not metoprolol [99]. A significant
inhibition of polarized transport of ABCB1 in CaCo-2
monolayers was observed for bisoprolol, carvedilol, and
propranolol, but not for metoprolol and sotalol [100].
Collectively, these data strongly suggest that ABCB1 is a
determinant of bisoprolol and carvedilol disposition in
humans and that the inhibition of its activity possibly
contributes to drug interactions, such as digoxin–carvedilol
or cyclosporine–carvedilol.
Recently, it was showed that aliskiren, the first drug in a
new class of renin inhibitors approved for the treatment of
hypertension, is an ABCB1 substrate, and that this may be
related to its relatively low bioavailability [6]. Moreover, both
atorvastatin and ketoconazole (known ABCB1 inhibitors),
when used at the maximum recommended dose, significantly
increased exposure to aliskiren [101]. However, aliskiren
presented no clinically significant drug interaction with
digoxin (an ABCB1 substrate) [101, 102]. These observations
suggest that co-administration of aliskiren with other ABCB1
substrates will probably not lead to harmful interactions, but
the co-administration of aliskiren with ABCB1 inhibitors
should be not recommended.
Several other drugs used in the treatment of hypertension
are substrates or inhibitors of ABC proteins.
Hydrochlorothiazide, a diuretic used worldwide, is a substrate
for ABCC4 [102]; the diuretic furosemide was shown to be
transported by ABCC1, ABCC2, and ABCC4 [102, 103];
olmesartan, a novel angiotensin II type 1 receptor antagonist,
is a substrate of ABCC2, and its prodrug olmesartan
medoxomil seems to be a substrate for ABCB1, ABCC2, and
ABCG2 [5]; and valsartan, a highly selective angiotensin II
type 1 receptor antagonist, is an ABCC2 substrate [104].
CONCLUSIONS AND PERSPECTIVES
Although initially the ABC proteins have been extensively
studied in other diseases, especially in cancer, their
importance to body homeostasis and their role in several
cardiovascular disorders is progressively being revealed. Over
the past two decades, pharmacogenetic research into human
drug-metabolizing enzymes has improved our knowledge
concerning drug interactions and individual susceptibility to
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ABC transporters in cardiovascular diseases
drug toxicity and efficacy. In the last few years, several studies
have focused on the clinical implications of genetic variations
in drug transporters, and this information may help in the
development of new drugs.
The involvement of ABC proteins in the genesis, maintenance,
and treatment of hypertension and atherosclerosis is just
beginning to be established. For instance, our understanding
of the importance of ABCA1 to cholesterol homeostasis is very
recent, but is increasing extremely fast. Also, the observed
interaction between CYP3A5 and ABCB1 genes and urinary
sodium excretion in humans [50] suggests a new pathway for
blood pressure regulation and has important implications
regarding the response to antihypertensive treatment. In
addition, the possible altered expression of ABCB1 observed in
hypertensive rats [38–40], if confirmed in humans, may have
major implications, including a possible contribution to the
reduced immune function and to altered drug, hormone, and
cytokine dispositions in hypertensive individuals, resulting in
unusual susceptibility to exogenous or endogenous toxins, as
well as to harmful drug interactions. For example, recent results
indicate that excessive dietary sodium ingestion greatly con-
tributes to resistance to antihypertensive treatment [105].
Funding: Our studies have been supported by grants from
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do
Rio de Janeiro, Programa de Oncobiologia/Fundação Ary Frausino
para Pesquisa e Controle do Câncer, Programa de Apoio aos Núcleos
de Excelência, and Conselho Nacional de Desenvolvimento Cientı́fico
e Tecnológico, Brazil.
Disclosure: The authors declare no conflict of interest.
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