Keywords
atherosclerosis - inflammation - lipid mediators - metabolic disorders - obesity
Introduction
The prevalence of overweight and obesity has reached epidemic proportions in Western
countries, but it is also rising in low- and middle-income countries. Globally, over
2 billion people are overweight, of which one-third suffer from obesity.[1]
[2]
[3]
[4]
[5] Obesity has been related to several chronic diseases including atherosclerosis,
hypertension, insulin resistance and other inflammatory diseases.[6]
[7] In particular, abdominal obesity is associated with increased incidence of cardiovascular
risk factors, which are elevated triglycerides, low high-density lipoprotein (HDL)
levels, increased blood pressure and hyperglycemia.[6] Apart from these metabolic complications, an important process that links obesity
to atherosclerosis and other cardiovascular diseases is chronic inflammation. The
endocannabinoid system is involved in the regulation of energy homeostasis and plays
a pathophysiological role in the development of visceral obesity and insulin resistance.[8]
[9] It has also arisen as a potential therapeutic target for cardiovascular diseases
including atherosclerosis, restenosis and myocardial infarction.[10] In addition to the well-established central and systemic effects of endocannabinoid
signalling, there is emerging evidence for a peripheral control of metabolic functions
in the liver, pancreas and adipose tissue based on cell-specific knockout models and
selective peripheral antagonists. An exciting novel tool for non-invasive imaging
of CB1 receptors has been recently reported, based on positron emission tomography/computer
tomography imaging of selective radioligand binding. As a proof of concept, enhanced
cardiac uptake of the radioactive CB1 ligand [11C]-OMAR was shown in obese mice as well as in humans with advanced obesity compared
with normal-weight subjects.[11] This technique may provide new insights into pathophysiological changes of CB1 signalling
during cardiovascular disease development not only in animal models, but also in the
clinical setting.
The role of the central endocannabinoid system in the regulation of metabolic homeostasis
and pathophysiological conditions has been extensively reviewed by others.[8]
[9]
[12]
[13] Here, we will focus on recent findings on peripheral endocannabinoid signalling,
which might be relevant for therapeutic approaches targeting vascular, immune cell,
liver as well as adipocyte cannabinoid receptors in atherosclerosis and related metabolic
dysfunctions.
The Endocannabinoid System
The Endocannabinoid System
The endocannabinoid system is an endogenous lipid signalling system that regulates
several pathways in the central nervous system and peripheral tissues. It plays an
essential role in the control of food intake and energy expenditure, energy homeostasis,
insulin sensitivity, as well as glucose and lipid metabolism and fat accumulation.[8] The endocannabinoid system comprises endogenous lipid mediators, the G protein-coupled
receptors (GPCRs) cannabinoid receptors 1 and 2 (CB1 and CB2) and enzymes involved
in endocannabinoid synthesis and inactivation.[8]
[10]
[14]
[15] In addition, other GPCRs sensitive to endocannabinoids have been described in the
last few years, which are GPR18, GPR55 and GPR119.[16] Endocannabinoids are arachidonic acid-derived bioactive lipids including anandamide
(AEA) and 2-arachidonoylglycerol (2-AG). These molecules are produced on demand by
tissues and circulating immune cells by the cleavage of membrane fatty acids ([Fig. 1]). The main synthesizing enzymes are N-acyl phosphatidylethanolamine-specific phospholipase
D (NAPE-PLD) for AEA and diacylglycerol lipase (DAGL) for 2-AG. AEA metabolism is
mainly catalysed via fatty acid amide hydrolase (FAAH) and 2-AG via monoacylglycerol
lipase (MAGL).[8]
[10]
[14]
Fig. 1 Main synthesis, degradation and signalling pathways of endocannabinoids. 2-AG, 2-arachidonoylglycerol;
AA, arachidonic acid; AEA, anandamide; cAMP, cyclic adenosinemonophosphate; CB1, cannabinoid
receptor 1; CB2, cannabinoid receptor 2; DAG, diacylglycerol; DAGL, diacylglycerol
lipase; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal-regulated
kinase 1/2; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAAA,
N-acylethanolamine acid amidase; NAPE, N-acylphosphatidylethanolamines; NAPE-PLD,
N-acyl phosphatidylethanolamine-specific phospholipase D; P38, p38MAPK subfamily;
PEA, palmitoylethanolamide; PI3K/Akt, phosphoinositide 3-kinase/protein kinase B;
PKC, protein kinaseC; TNFR, tumor necrosis factor receptor.
There is increasing clinical evidence that enhanced endocannabinoid system activation
is associated with metabolic disorders, in particular abdominal obesity, dyslipidemia,
insulin resistance, as well as atherosclerosis.[14] Circulating endocannabinoid levels are elevated in patients with coronary artery
disease[17] and in obese individuals compared with lean individuals,[18] and positively correlate with parameters such as body fat and visceral fat mass,
as well as with circulating triglyceride levels.[18]
[19]
[20] There is also a positive correlation between circulating endocannabinoid levels
in obese individuals and coronary endothelial and circulatory dysfunction.[21]
[22] Moreover, CB1 expression is increased in the myocardium of obese individuals and
epicardial adipose tissue from ischaemic subjects as well as in human atherosclerotic
plaques of unstable versus stable angina patients.[11]
[17]
[23] The CB1 inverse agonist rimonabant, which was tested and approved for the treatment
of obesity, was withdrawn for clinical use due to the elevated incidence of central
side effects such as depression.[24] Nevertheless, the available clinical data indicate that inhibition of CB1 signalling
may improve cardiovascular risk factors in obese patients.[13]
[25]
The Endocannabinoid System and Atherosclerosis: Modulation of Endothelial Cell Activation
and Leukocyte Recruitment
The Endocannabinoid System and Atherosclerosis: Modulation of Endothelial Cell Activation
and Leukocyte Recruitment
Atherosclerosis is characterized by a chronic inflammation of the arterial wall with
subendothelial plaque formation.[26] The healthy endothelium plays a critical role in maintaining the vascular wall homeostasis
and circulatory function. It represents a relatively impermeable, anti-thrombotic
and anti-adhesive blood–tissue interface, which regulates vascular resistance by releasing
vasoactive factors such as nitric oxide (NO). Endothelial NO is not only a vasodilator,
but it also inhibits platelet aggregation, leukocyte adhesion, endothelial permeability,
low-density lipoprotein (LDL) oxidation and smooth muscle cell proliferation.[27] Inflammatory, biochemical and physical factors (including hyperlipidaemia, turbulent
flow, high blood pressure and cigarette smoking) induce endothelial dysfunction by
inhibiting NO release and increasing endothelial permeability.[26] This is the initiating step in the development of atherosclerosis, which leads to
the accumulation of LDL and leukocytes in the subendothelial space as a consequence
of augmented vessel permeability and up-regulation of endothelial adhesion molecules.[26] Within the subendothelial space, the LDL is modified to oxidized LDL (oxLDL) which
further triggers the inflammatory process. OxLDL is engulfed by infiltrating monocytes
through scavenger receptors such as CD36 or SR-A1 and stored in lipid droplets in
the esterified form, which leads to foam cell formation and enhanced release of pro-inflammatory
cytokines.[28]
Role of Classical Cannabinoid Receptors and Endocannabinoids
An increasing number of experimental studies highlight the relevance of endocannabinoid
signalling in these early stages of atherosclerosis development ([Fig. 2]). Blocking endogenous endocannabinoid signalling by pharmacological CB1 blockade
with the CB1 inverse agonist rimonabant improved the endothelium-dependent vascular
response in isolated aortic rings of apolipoprotein E knockout (ApoE−/−) mice.[29] In primary human coronary artery endothelial cells, CB1 activation with AEA or a
synthetic CB1-selective agonist induced endothelial cell death, reactive oxygen species
production and related intracellular signalling pathways, which was attenuated by
CB1 antagonists.[30] While rimonabant failed to limit atherosclerotic plaque growth in the ApoE−/− model,[29] its chronic oral administration reduced plaque development in the LDL receptor knockout
(Ldlr−/−) mouse model of atherosclerosis, accompanied by reduced weight gain and improved
plasma lipid profiles.[31] The different findings might be related to the genetic mouse models, diet composition,
rimonabant dosage and/or route of administration.
Fig. 2 Effect of endocannabinoids and cannabinoid receptor (CB1, CB2, and GPR55) activation
in endothelial cells, monocytes, neutrophils and smooth muscle cells. 2-AG, 2-arachidonoylglycerol;
AEA, anandamide; CB1, cannabinoid receptor 1; CB2, cannabinoid receptor 2; GPR55,
G protein couple receptor 55; PEA, palmitoylethanolamide.
Synthetic or plant-derived cannabinoids have been shown to exhibit anti-atherogenic
properties by limiting plaque macrophage accumulation, pro-inflammatory cytokine release
and adhesion molecule expression.[32]
[33]
[34] Additional blocking experiments with CB2 antagonists indicated that these anti-inflammatory
effects are mediated by CB2 signalling.[33]
[34] The atheroprotective role of CB2 was further strengthened by experimental studies
employing selective CB2 agonists or mice lacking Cnr2 (the gene encoding CB2) on ApoE−/− as well as Ldlr−/− background.[35]
[36] One study failed to reproduce the anti-inflammatory effects of CB2 activation in
the Ldlr−/− mouse model.[37] In view of a potential relevance for human pathophysiology, in vitro experiments
with primary human coronary endothelial cells and smooth muscle cells confirmed anti-inflammatory
and anti-proliferative effects of CB2 stimulation.[38]
[39]
In support of a causal role for endocannabinoid signalling in atherosclerosis, experimental
data in atherosclerotic mouse models suggest that genetic ablation or pharmacological
inhibition of FAAH, the endocannabinoid AEA metabolizing enzyme, may promote the development
of unstable plaques[40]
[41] and enhanced neointima formation after arterial injury.[42] The pro-atherogenic effect of the FAAH inhibitor was mediated, at least in part,
by an increased arterial neutrophil recruitment ([Fig. 2]).[40] The enhanced neutrophil recruitment to atherosclerotic vessels might be due to the
increased chemokine CXCL1 production in plaques of Faah−/− mice or mice treated with FAAH inhibitor, respectively, but it may also involve
additional mechanisms.
An opposite effect on atherosclerotic plaque development has been reported when targeting
the endocannabinoid 2-AG metabolizing enzyme MAGL. Mice with genetic deficiency of
Magl on ApoE−/− background and 9 weeks of Western-type diet feeding developed larger but more
stable plaques with increased smooth muscle cell and collagen content as well as thicker
fibrous caps, whereas plaque lipid and macrophage content were reduced ([Fig. 2]).[43] Treatment with a CB2 inverse agonist prevented the observed plaque phenotype in
ApoE−/− Magl−/− mice, suggesting that inhibiting the MAGL pathway exhibits anti-inflammatory effects
via enhanced 2-AG/CB2 signalling.[43] CB2 is predominantly expressed by immune cells and is considered to play an anti-inflammatory
and atheroprotective role.[32]
[35]
[44] The effect of genetic MAGL deficiency on early atherosclerotic plaque formation
was not addressed in the initial study.[43] Using a pharmacological inhibitor of MAGL, Jehle et al recently reported that inhibiting
this enzyme during early atherogenesis promotes plaque formation.[45] ApoE−/− mice were treated for 4 weeks with the MAGL inhibitor JZL184 in parallel to 4
weeks high-fat diet feeding. The analysis of atherosclerotic plaques in aortic root
cross-sections revealed significantly larger plaques and more aortic macrophages in
mice treated with MAGL inhibitor compared with vehicle-treated mice.[45] This seems somewhat conflicting with the reported anti-atherosclerotic effects in
ApoE−/− Magl−/− mice at advanced stage.[43] As opposed to Jehle et al, our own recent data support an atheroprotective effect
of genetic Magl deficiency or pharmacological blockade of this enzyme. In our experimental study,
blocking the MAGL pathway during atherosclerosis onset led to CB1 desensitization,
which translated into an atheroprotective B1a-IgM phenotype.[46] The atheroprotective effect was dependent on CB2 signalling, as confirmed in Cnr2−/− mice. It is possible that the efficiency of MAGL inhibition (depending on the
selected dose, way and frequency of administration) in the study from Jehle et al
is less potent than global genetic deficiency of the enzyme or the higher dose of
the MAGL inhibitor used in our study. A varying efficiency of MAGL inhibition may
differentially affect cannabinoid receptor signalling or cannabinoid receptor-independent
actions related to altered eicosanoid levels.[47] As to a possible modulation of cannabinoid receptor signalling, it has been shown
that genetic deficiency or chronic MAGL inhibition results in CB1 desensitization,
due to chronically elevated 2-AG levels,[48]
[49] and this was also observed in our own experimental atherosclerosis study targeting
MAGL.[46] In support of dose-dependent effects of MAGL inhibition, it has been previously
reported that CB1 receptor activity and expression are attenuated following high-dose
JZL184 administration (16 or 40 mg/kg), but are maintained at low-dose JZL184 treatment
(1.6, 4 or 8 mg/kg).[50] The putative role of 2-AG in atherosclerosis becomes even more complex when considering
the effect of genetic Dagl deficiency, the gene encoding a major 2-AG biosynthetizing enzyme. Myeloid cell-specific
deletion of the Dagl isoform α in the ApoE−/− background inhibited atherosclerotic plaque formation.[51] Given that DAGLα is more relevant for brain 2-AG production than DAGLβ, while the
latter is more important for liver 2-AG release,[52] it would be interesting to further address the relevance of DAGLβ in atherosclerosis,
which might be the more relevant isoform in cardiovascular disease. In support of
this hypothesis, online accessible murine microarray data from the Immunological Genome
Project (www.immgen.org) show much higher expression levels of the DAGLβ isoform than DAGLα in myeloid cells.
Possible Role of Cannabinoid-Sensitive Receptor GPR55 in Atherosclerosis
So far, little is known about the contribution of other cannabinoid-sensitive receptors
in atherosclerosis. The orphan receptor GPR55 has been proposed as a novel cannabinoid
receptor, based on high-affinity binding to synthetic cannabinoid CP55940 in radioactive
ligand binding assays with the cloned human receptor.[53] GPR55 was also found to exhibit high binding affinities for endogenous ligands,
including endocannabinoid-related palmitoylethanolamide (PEA) as well as endocannabinoids
AEA and 2-AG.[53] However, further investigation revealed that lysophosphatidylinositols were more
potent endogenous ligands than endocannabinoids.[54] According to quantitative polymerase chain reaction data, GPR55 is highly expressed
in the brain, adrenals, small intestine and, to a lower extent, in the spleen.[53] The flow cytometric analysis of GPR55 surface levels on human blood leukocytes revealed
high receptor expression by monocytes and natural killer cells.[55] In vitro data with THP1-derived macrophages further suggest a role for GPR55 in
macrophage oxLDL accumulation.[56] Montecucco et al tested the effect of chronic treatment with the GPR55 antagonist
CID16020046 on atherosclerosis in ApoE−/− mice fed with either a normal chow diet for 16 weeks or a high cholesterol diet
for 11 weeks.[57] Independent of normal or atherogenic diet, the plaque size was not affected by CID16020046
although in both experimental setups intra-plaque MMP-9 was increased, while the collagen
content was reduced compared with the vehicle-treated group. Only in mice fed with
normal chow diet, which develop less advanced atherosclerotic lesions, treatment with
CID16020046 resulted in plaques with higher neutrophil content ([Fig. 2]). Mechanistically, they found that the GPR55 antagonist systemically increased the
circulating levels of chemokines mediating neutrophil recruitment under normal diet
conditions and induced neutrophil degranulation in vitro. These findings may suggest
that GPR55 negatively regulates neutrophil chemotaxis and activation through still
unknown mechanisms. However, the effects of GPR55 on atherosclerosis might be masked
under high-fat diet conditions, at least in this specific experimental study.[57]
More recent findings propose that GPR55 might also play a role at advanced stages
of atherosclerosis, by modulating macrophage-resolving properties.[58] GPR55 is a possible receptor for mediating anti-inflammatory effects of the endocannabinoid-related
lipid mediator PEA. In the ApoE−/− mouse model, PEA treatment inhibited plaque formation at early stage and promoted
signs of plaque stability in pre-established atherosclerosis as evidenced by reduced
macrophage accumulation and necrotic core size, increased collagen deposition and
down-regulation of pro-inflammatory macrophage markers.[58] In vitro experiments with bone marrow-derived murine macrophages revealed that PEA
increased the expression of the phagocytosis receptor MerTK and enhanced macrophage
efferocytosis, which was blunted in Gpr55-deficient macrophages obtained from knockout mice.[58]
Endocannabinoid System and Lipid Metabolism
Endocannabinoid System and Lipid Metabolism
Hepatic and Bile Acid Lipid Metabolism
Mice with genetic deficiency of Magl on ApoE−/− background not only develop less atherosclerosis, but also have an altered hepatic
cholesterol metabolism and lipid-dependent gut transit.[59] These mice develop less pronounced liver steatosis upon Western-type diet feeding.
Under fasting conditions, a reduced level of plasma-free glycerol concentrations and
free fatty acids was found in Magl−/− ApoE−/− mice compared with ApoE−/− controls, as well as reduced hepatic triglyceride levels and reduced very low
density lipoprotein (VLDL) secretion. However, there were no changes in fasting plasma
levels of triglycerides and total cholesterol, and no effect on body weight after
atherogenic diet feeding. These findings suggest that Magl-deficient mice exhibit a moderate lipolytic defect. The reduced hepatic lipid levels
were not due to altered liver cholesterol synthesis or uptake, but rather a consequence
of increased intestinal cholesterol secretion via bile acid and reduced bile acid
re-uptake.[59] The authors suggest an involvement of effects which are independent of CB1, although
they did not specifically clarify which receptors are involved in the hepatic effects
of Magl deficiency. However, it is conceivable that CB1 desensitisation contributes at least
partially to the metabolic changes, given that hepatic Cnr1 mRNA expression was not detectable in Magl−/− ApoE−/− mice.[59] This may also explain the absence of Cnr1 expression in ApoE−/− mice fed with atherogenic diet, as a consequence of increased 2-AG endocannabinoid
levels.[40]
[60] There is additional experimental evidence reporting that hepatic CB1 activation
increases bile acid synthesis.[61] Moreover, hepatic CB1 stimulates fatty acid synthesis and thereby mediates hepatic
steatosis and related metabolic dysfunction[62] ([Fig. 3]).
Fig. 3 Peripheral and metabolic effects of CB1 signalling. CB1 signalling affects several
peripheral organs. In liver, CB1 activation leads to stimulation of bile/fatty acid
synthesis, the accumulation of TG and the reduction of ApoA1 secretion, which result
in decreased HDL and increased TG levels in circulation. Besides, CB1 activation stimulates
fatty acid synthesis also in adipose tissue. In macrophages, CB1 stimulation causes
intracellular cholesterol accumulation as a consequence of increased uptake (CD36)
and decreased efflux (ABCA1). In pancreas, CB1 activation in infiltrating macrophages
directly activates the NLRP3 inflammasome leading to β cell loss. In the kidney, CB1
signalling in podocytes has been linked to glomerular and tubular dysfunction and
fibrosis. ABC, ATP-binding cassette transporter; ApoA1, apolipoprotein A1; CB1, cannabinoid
receptor 1; HDL, high-density lipoprotein; NLRP3, NLR family pyrin domain-containing
3; TG, triglycerides.
Obesity is associated with increased circulating endocannabinoid levels and decreased
HDL.[6] To clarify whether endocannabinoids reduce HDL by inhibiting the expression of its
primary structural lipoprotein apolipoprotein A1 (ApoA1), in vitro experiments with
human hepatocyte and intestinal epithelial cell lines have been performed. Indeed,
treatment of HepG2 and Caco-2 cells with AEA or 2-AG reduced ApoA1 secretion in these
cells.[63] The endocannabinoid-mediated reduction of ApoA1 provides a mechanistic explanation
for the decreased HDL levels in obese individuals. To further address the link between
elevated endocannabinoid levels and lipid metabolism, other investigators used a pharmacological
in vivo approach to inhibit endocannabinoid metabolism. They found that increased
endocannabinoid levels through inhibition of their enzymatic hydrolysis by isopropyl
dodecylfluorophosphonate resulted in elevated plasma triglyceride levels, which were
associated with reduced plasma triglyceride clearance.[64] The effect was mediated via CB1 signalling, which was confirmed with Cnr1−/− mice and additional experiments with CB1 antagonists.
Macrophage Cholesterol Metabolism
OxLDL which accumulates in atherosclerotic plaques is taken up by macrophages via
scavenger receptors.[28] The cholesterol may be stored as intracellular lipid droplets or transported out
of the cell via ABCA1 and ABCG1 to ApoA1 or HDL. This process is named reverse cholesterol
transport. In vitro data indicate that oxLDL increases endocannabinoid signalling,
which in turn decreases reverse cholesterol transport.[65] In particular, oxLDL was shown to increase 2-AG and AEA levels as well as CB1 and
CB2 expression in RAW264.7 and rat peritoneal macrophages. The synthetic cannabinoid
WIN55,212–2 reduced the expression of ABCA1 in RAW264.7 cells, while increasing scavenger
receptor CD36. This resulted in increased cellular cholesterol levels in RAW264.7
macrophages. The effect was sensitive to pretreatment with CB1 antagonist and inverse
agonist AM251, which indicates a possible pathophysiological mechanism by which CB1
signalling may contribute to atherosclerotic plaque inflammation. Macrophage stimulation
with the endocannabinoid-related endogenous mediator PEA resulted in an up-regulation
of SR-B1 levels, a receptor mediating bidirectional lipid transport in macrophages.
This effect was independent of GPR55 and might be mediated by PPAR-α.[58]
Excessive cholesterol accumulation impairs the capacity of macrophages to clear apoptotic
cells and may lead to the formation of cholesterol crystals that are able to induce
NLRP3 inflammasome activation.[66] In an experimental model of type 2 diabetes, CB1 was shown to directly activate
the NLRP3 inflammasome complex in pancreas-infiltrating macrophages, thereby contributing
to β cell loss.[67] Moreover, impaired clearance of apoptotic cells, leading to secondary necrosis,
and extracellular lipid accumulation contribute to the formation of a necrotic core.
Secondary necrosis as well as alternative non-apoptotic cell death pathways occurring
within advanced lesions further entrain the local inflammatory milieu, thereby contributing
to plaque destabilization.[68] Freeman-Anderson and colleagues investigated the effect of genetic CB2 deficiency
on oxLDL-induced apoptosis and found that the apoptosis rate was significantly reduced
in peritoneal macrophages lacking CB2.[69] Mechanistically, the deactivation of the Akt pro-survival pathway was impaired in
the absence of CB2 after 7-ketocholesterol exposure, suggesting that CB2 expression
increases the susceptibility of macrophages to oxLDL-induced apoptosis. However, a
potential relevance of this mechanism in atherosclerotic plaque macrophages has not
been confirmed thus far.
Evidence for a Peripheral Endocannabinoid Regulation of Lipid and Glucose Metabolism
Evidence for a Peripheral Endocannabinoid Regulation of Lipid and Glucose Metabolism
Peripherally active CB1 antagonists have been shown to improve metabolic disorders
in mouse models without blocking central CB1 receptor signalling.[67]
[70]
[71]
[72]
[73] These drugs do not pass the blood–brain barrier and therefore are devoid of centrally
mediated psychiatric side effects, such as anxiety and depression.[74]
[75] In addition, experimental evidence based on cell-specific genetic deficiency of
CB1 receptors is emerging that strengthens the relevance of peripheral endocannabinoid
regulation in metabolic functions ([Fig. 3]). Liver-specific Cnr1 deficiency blunted glucocorticoid-induced dyslipidemia, but not the obesity phenotype.[71] More recently, inducible adipocyte-specific Cnr1 deficiency was shown to be sufficient for protecting mice from diet-induced obesity
and associated metabolic alterations. Moreover, induction of adipocyte-specific Cnr1 deficiency in mice with already established obesity reversed the phenotype in these
mice.[76] Podocyte-specific deletion of Cnr1 prevented glomerular and tubular dysfunction in a mouse model of diabetic nephropathy.[77] As mentioned above, CB1 signalling in pancreatic macrophages induces β cell loss
in type 2 diabetes by activating the NLRP3 inflammasome complex.[67] A limitation is that the experimental in vivo evidence in this study was solely
based on combined treatment with peripherally active CB1 antagonists and clodronate
liposomes for macrophage depletion or siRNA-mediated Cnr1 knockdown, respectively.
Conclusion
Emerging evidence suggests that enhanced endocannabinoid signalling affects atherosclerosis
via multiple effects, including a modulation of vascular inflammation, leukocyte recruitment
and macrophage cholesterol metabolism, which influences atherosclerotic plaque stability.
A few experimental studies revealed somewhat conflicting findings, which might be
partly related to the pharmacology of available cannabinoid compounds, which can act
as agonists, partial agonists, inverse agonists or antagonists for several cannabinoid
receptors.[15] The biological response to the stimulation with a synthetic cannabinoid receptor
agonist also depends on the presence of endogenously produced ligands in response
to cellular activation. Despite some controversy in pro- or anti-inflammatory effects
of inhibiting selective enzyme pathways of endocannabinoid metabolism, there is overwhelming
evidence for a pathophysiological role of excessive CB1 activation by endocannabinoids
in atherosclerosis and related metabolic complications. Thus, blocking CB1 signalling
in the vasculature and peripheral organs might represent a promising therapeutic target
in atherosclerosis. As opposed to other emerging anti-inflammatory drugs for the treatment
of atherosclerosis, blocking CB1 signalling might offer the advantage to exhibit multiple
anti-atherogenic actions by inhibiting vascular inflammation and improving metabolic
risk factors.
