Introduction
Cardiovascular disease (CVD) is a global epidemic representing the leading cause of
death in some Western countries. According to the American Heart Association, a total
of 92.1 million US citizens currently have ≥1 forms of CVD, with numbers expected
to grow reaching up to 43.9% of the US population by 2030. In 2013, 17.3 million people
(≈31% of all deaths) died due to CVD, and the number is expected to rise to at least
23.6 million in the next 15 years and cause an estimated economic burden of 1.0 trillion
US dollars by 2030.1
Given its pathological and economic burden, there is a striking need for both mechanistic
insights into CVD and the development of avenues for therapy. This review highlights
the potential of cannabinoids and their receptors as targets for intervention. The
endocannabinoid system (ECS) is upregulated in cardiovascular disease states, and
cannabinoids in general influence disease progression.2 Moreover, there are paradoxical
indications as to whether therapies directed at the ECS, or exogenous drugs derived
from marijuana, could have therapeutic impact in CVD.
The recent changes in the legalization of cannabis for both medical and recreational
use has made cannabis consumption almost as conventional as tobacco use (Hall et al).
This makes understanding the long‐term effects of cannabis, whether harmful or beneficial,
imperative. While acute adverse effects (impairment of memory, coordination and judgement)
are widely accepted, most studies on long‐term use and effects have been inconclusive.3,
4, 5, 6, 7 These inconclusive results could possibly be due to the barriers in conducting
cannabis research such as: access to the quality and quantity of cannabis needed for
research as well as cannabis being classified as a Schedule 1 substance.7 Other difficulties
of long‐term population studies also include separating tobacco users from marijuana
users, as these two usually coincide. For example, recent publications from the CARDIA
(Coronary Artery Risk Development in Young Adults) cohort study concluded no significant
association with neither marijuana use and CVD or atherosclerosis risk.5, 6 Furthermore,
in the CARDIA study looking at the association of smoking marijuana to atherosclerosis,
only the subjects that smoked both marijuana and were tobacco users showed an associated
risk with subclinical atherosclerosis.6 Even with current challenges and knowledge
gaps in cannabis research there has been some strong evidence for cannabis having
therapeutic roles in treating everything from pain, and muscle spasms in multiple‐sclerosis
patients, to reducing nausea in chemotherapy patients.7 This evidence, along with
the knowledge of the ECS being upregulated in CVD, makes it an attractive therapeutic
target for CVD.
This literature begins by reviewing CVD, including the contributing pathologies within
CVD, and current therapeutic approaches. That is followed by the review of the ECS
and its physiological and pathological roles, and details the receptors involved in
the ECS. Finally, we discuss the connection of CVD to the ECS and delve into the possible
manipulations of these pathways that could be employed for future therapeutic approaches.
Contributing Pathologies Within the CVD Spectrum
Coronary Artery Disease
Coronary arteries are crucial in supporting the myocardium with oxygen‐rich blood.
When low‐density lipoproteins (LDL), macrophages, and lymphocytes accumulate within
the artery wall (triggered by different environmental, behavioral, and genetic risk‐factors)
they form lesions. Over decades, necrotic cells and cholesterol accumulate to form
hardened plaques, which leads to a complex, chronic inflammatory disease known as
coronary artery disease (CAD) or atherosclerosis.8 When the thrombogenic plaque material
ruptures and blood clots form on the plaque, it eventually leads to spontaneous temporary
loss of blood supply, a condition known as unstable angina. Contrasting with stable
angina, these periods are spontaneous and not exercise‐induced. Symptoms include chest
pain, a feeling of pressure or tightness in the chest, and shortness of breath. When
the thrombus completely blocks the vessel (thrombosis), or a part breaks off (embolization)
blocking off a smaller downstream blood vessel, a myocardial infarction occurs which
permanently damages heart muscle tissue and can lead to death.
Ischemia/Reperfusion Injury
Myocardial ischemia‐reperfusion injury (IRI) is the result of restricted blood supply
to tissues which causes a shortage of oxygen (ischemia) and the resulting injury of
the myocardium caused by the restoration of coronary blood flow (reperfusion). It
is an acute complication of atherosclerosis9 that can also be caused by, or associated
with, hypertension, hyperlipidemia, diabetes mellitus and insulin resistance, and
aging. The condition results in a pattern of structural and metabolic changes, and
leads to irreversible injury of the myocardium.10 Myocardial IRI may lead to myocardial
infarction, cardiac arrhythmias, and contractile dysfunction.11 The risk for developing
myocardial IRI is higher for males, and also includes: diabetes mellitus, dyslipidemia,
hypertension, insulin resistance, nutritional deficits, and physical inactivity; as
well as smoking, high total cholesterol and low HDL, and high blood pressure.1, 12
Hypertension
A person is defined to be hypertensive when blood pressure is 140 mm Hg systolic,
or exceeds this value, and/or when it is 90 mm Hg diastolic or higher.13, 14 Most
people having their first stroke have a blood pressure higher than 140/90 mm Hg.13
A condition commonly caused by hypertension, as well as heart valve stenosis, is cardiac
hypertrophy. An estimated 85.7 million (34%) of the American population aged ≥20 years
is hypertensive. The prevalence of high blood pressure increases with age and is highest
among African Americans (45.0% of males, and 46.3% of females are hypertensive, compared
with 34.5% of white males and 32.3% of white females). By 2030, an estimated 41.1%
of American adults will be hypertensive.1 While 76% of hypertensive patients in the
United States use antihypertensive medication, only 54.4% can control the condition.1
Hypertrophy
Cardiac hypertrophy is an adaptive and compensatory response of the heart to maintain
cardiac function, although the cardiac muscle cells must work harder.15 It is characterized
by a higher rate of protein synthesis, a decrease in size of the heart chamber, and
thickening of left and right ventricular walls; as a result, poses as a major risk
factor of developing arrhythmia and heart failure.1, 16
Endothelial Dysfunction
Coronary vascular tone is regulated by endothelial cells releasing multiple vasoactive
compounds that act on smooth muscle cells,17 including nitric oxide, prostacyclin
, substance P, and cytochrome P450 monooxygenase (CYP450) metabolites of arachidonic
acid. These autacoids are responsible for vasorelaxation of the endothelium in the
vasculature.17, 18 Early atherosclerosis is marked by endothelial dysfunction caused
by biochemical and physical injuries, as well as immune‐mediated damages and oxidative
stress; resulting in altered platelet and leukocyte adhesion to the vascular surface,
initiating an inflammatory response in the artery wall.9, 19 The activated endothelial
cells locally produce chemokines, chemokine receptors, and adhesion molecules, eg,
Vascular cell adhesion protein 1 (V‐CAM‐1), Intercellular Adhesion Molecule 1 (ICAM‐1).20
Inflammatory cells cause leukocyte rolling and cell adhesion along the vascular surface,
which secrete chemokines and cytokines, resulting in chronic vascular inflammation.9
Oxidative Stress
Oxidative stress is a common factor across all contributing pathologies in CVD.21
Oxidative stress arises when the production of reactive oxygen species exceeds the
total antioxidant capacity of the body. Reactive oxygen species act as second messengers
in signaling cascades in the cardiovascular system and are produced by cardiac mitochondria.22,
23 When the concentration of reactive oxygen species exceeds total antioxidant capacity,
damage can be caused to biomolecules, eventually leading to loss‐of‐function and cell
death. There are several cardiovascular risk factors that aid in promoting oxidative
stress: poor diet, diabetes mellitus, obesity, smoking; as well as excessive environmental
pollution.23
Current Therapeutic Approaches to CVD
Prevention
Epidemiologic studies show that there is a 2‐fold increased risk for development of
CAD and hypertension associated with a physically inactive lifestyle.12 Patients exercising
on a regular basis after having a myocardial infarction lower the risk of death by
20% to 25% compared with controls. Patients with established CAD can improve symptoms
of angina and congestive heart failure, as well as reducing the severity of exercise‐induced
ischemia. Regular exercise reduces systolic and diastolic blood pressure, decreases
total and LDL cholesterol, and increases HDL cholesterol.12, 24
A plant‐based diet can help prevent and even reverse CAD. The Lifestyle Heart Trial
found a reduction in regression of atherosclerosis, reduction in frequency of angina
episodes (91% of patients), and a reduction in LDL (37.2%) similar to that accomplished
by LDL‐lowering medication.12, 25 Coronary events are reduced by 73%, and 70% decrease
in all‐cause mortality in the plant‐based group compared with the control group that
were given the recommended American Heart Association diet; 53% of the control group
had progression of atherosclerosis.12, 25
Management and Treatment
There are different options that patients can consider for treating CAD, and hypertension.
Natural treatments include lifestyle changes: increase physical activity, changing
to a healthy diet, losing excess weight, cessation of smoking, and stress reduction.
Drug regimens center around antihypertensive agents (angiotensin‐converting‐enzyme
inhibitors angiotensin receptor 2 blockers), 3‐hydroxy‐3‐methylglutaryl‐coenzyme A
inhibitors or statins, beta‐blockers, or blood‐thinning medication.12, 25, 26 Statins
have been the most prescribed drug class in the United States and are used to treat
hypercholesterolemia by lowering LDL cholesterol, apolipoprotein B, very low‐density
lipoprotein (VLDL), and plasma triglycerides. This is done by inhibiting the enzyme
responsible for cholesterol synthesis catalysis, 3‐hydroxy‐3‐methylglutaryl‐coenzyme
A reductase.26, 27 Statins have proven to significantly decrease the number of cardiovascular
events due to their anti‐inflammatory and immunomodulatory effects.9 Moreover, they
are well‐tolerated by most patients, but can have dose‐dependent muscle‐related adverse
effects (myopathy) where the levels of plasma creatine kinase are 10 times higher
than normal.28 This condition goes along with pain, tenderness, weakness, and restriction
in mobility.28, 29 The human monoclonal antibody, alirocumab, inhibiting proprotein
convertase subtilisin‐kexin type 9 (PCSK9), was found to decrease LDL levels in patients
by 62% when added to a statin therapy.30
Ischemic preconditioning uses the transient induction of controlled and non‐lethal
myocardial low‐flow ischemia and reperfusion to achieve cardio‐protection. The ECS
is activated by heat or bacterial lipopolysaccharides (LPS), and 2‐arachidonoglycerol
(2‐AG) levels are increased.31 2‐AG, but not anandamide, provides protection in isolated
perfused rat hearts by reducing infarct size and myocardial damage.31 The activation
of CB2 receptors confers immediate protection against a subsequent prolonged and injurious
period of ischemia.31, 32 Furthermore, ischemic preconditioning has a protective effect
on diabetic and aging hearts.33
Angiotensin‐converting‐enzyme inhibitors and angiotensin receptor 2 blockers, such
as ramipril and telmisartan, are used to treat hypertension by either competitive
inhibition of ACE—which prevents the conversion of AT1 to AT2, or by blocking type
1 angiotensin 2 receptors on blood vessels to avoid binding of angiotensin 2. Both
are powerful vasoconstrictors, however most of the patients do not achieve recommended
blood pressure targets and remain at high cardiovascular risk and experience adverse
effects like coughing.
The Endocannabinoid System
Physiological and Pathophysiological Roles of the ECS
The ECS is implicated in a great number of physiological processes. At the cellular
level, the ECS controls cell proliferation, differentiation, cell survival, and apoptosis
in different tissues such as adipose tissue,34 epithelial cells, bone, blood, gonads,
as well as the brain.35, 36 Endocannabinoids are synthesized in the central nervous
system and regulate pain perception, motor functions, control of tremor and spasticity,
learning, memory, thermogenesis, regulation of weak/sleep cycles, axonal pathfinding,
synaptic plasticity, emotional behavior, stress response, feeding and appetite, reproductive
function, and sex behavior. Besides the brain, endocannabinoids can be synthesized
and function in peripheral tissues eg, the heart, GI tract, blood cells, adipose tissue,
muscle, liver and pancreas; where they influence inflammatory responses, platelet
aggregation, blood pressure, heart rate, vasodilatation, and energy balance.36, 37,
38 Consequently, the endocannabinoid system is involved in many pathologies and can
be correlated to neurodegenerative disorders, obesity, diabetes mellitus, cardiovascular
disorders, cancer, and inflammatory processes.35, 37, 38
Endocannabinoids and Their Receptors
The endocannabinoid signaling system emerged as a potential therapeutic target over
the past years. In focus are the ∆9‐THC mimicking hydrophobic polyunsaturated fatty
acid derivatives, anandamide and 2‐AG, that bind and functionally activate one or
both cannabinoid receptor subtypes (CB1 and CB2), as well as other receptors. Endocannabinoids
are synthesized on demand in response to increased intracellular calcium concentrations
or stimulated by metabotropic glutamate receptors located on postsynaptic neurons.
Anandamide and 2‐AG
Anandamide was the first endogenously produced cannabinoid to be discovered in 1992.31,
39 The precursor for anandamide synthesis is the phospholipid N‐arachidonoyl phosphatidylethanolamine,
and the process is mediated by hydrolytic release of polyunsaturated acids by a phospholipase.31,
40, 41 Generally, anandamide has a low overall efficiency and acts as partial agonist
for CB1 and vanilloid TRP receptors and it also binds weakly to CB2 receptors.42 Metabolism
of anandamide happens rapidly by fatty acid amide hydrolase (FAAH).31, 43 2‐AG was
discovered shortly after anandamide in 1995.44, 45 It is synthesized by the enzyme
diacylglycerol lipase from arachidonic acid‐containing diacylglycerol and metabolized
by soluble monoacylglycerol lipase.31, 46 Compared with anandamide, 2‐AG is produced
in much higher numbers and binds potently to CB1 and CB2, but not to vanilloid receptor.47
Binding results in retrograde (post to pre‐synaptic) signaling and an inhibition of
adenylate cyclase, as well as blocking of voltage‐gated N‐type calcium channels, which
have important functions in the central nervous system and chronic and neuropathic
pain perception.
Metabotropic Cannabinoid Receptors
The cannabinoid (CB) receptors CB1 and CB2 are both members of the superfamily of
metabotropic G‐protein‐coupled receptors (GPCRs), and have been cloned and identified
in the human, rat, and mouse myocardium.40, 43, 48 The cannabinoid receptors are present
in high abundance throughout the body where they, and their ligands, are involved
in many important physiological functions and interactions with other neurotransmitters.31,
46
CB1 receptors are abundant metabotropic G‐protein‐coupled receptors found predominantly
in neurons of the brain at regions associated with higher cognitive functions, movement
control, motor and sensory functions of the autonomic nervous system, and neurotransmission
modulation.31, 49 In addition, CB1 receptors also function in the peripheral nervous
system: in vascular and cardiac tissue, adipocytes, liver, GI tract and uterus to
regulate basic physiological mechanisms such as energy balance and reproduction.48,
50, 51 The CB1 receptor also has influence on memory and learning behavior, plays
a role in addiction processes, and mediation of the psychoactive effect of Tetrahydrocannabinol
(THC).52, 53 Signal transduction happens through the interaction with G proteins to
inhibit adenylyl cyclase, activate mitogen‐activated protein kinases, inhibit voltage‐gated
Ca2+ channels, and activate K+ currents; as well as to influence nitric oxide signaling.49,
53 CB1 agonists include: ∆‐9‐THC, endogenous anandamide, 2‐AG, 2‐Arachidonoyl dopamine;
and highly potent HU210, CP55940 and CP55244. Antagonists include: rimonabant, and
structurally similar antagonists like AM241, taranabant, ACHSR, and AM4113.53 CB1
receptors can be co‐expressed with CB2 receptors.
CB2 receptors were first identified on macrophages and are also expressed on mast
cells, B cells, some blood cells, and in the peripheral nervous system like the tonsils
and thymus, and mediate cannabinoid‐induced immune modulation.9, 40, 49 Like CB1 receptors,
CB2 receptors belong to class A serpentine receptors that are coupled to G proteins,
and modulate pathways of adenylyl cyclase, mitogen‐activated protein kinases, extracellular
signal‐regulated kinases 1/2 (ERK1/2), some Ca2+ and K+ ion channels, and nuclear
factors of activated T‐cells and B‐cells.52 2‐AG is considered a primary agonist of
CB2 receptors. Exogenous cannabinoids like THC and cannabinol and synthetic cannabinoids
including WIN‐55212‐2 and CP55940 have also been described to bind to CB2.54
Ionotropic Cannabinoid Receptors (TRPV1)
The transient receptor potential cation channel subfamily V, member 1 (TRPV1) is an
ionotropic non‐selective cation channel that is predominantly expressed in peripheral
sensory neurons and widespread in the cardiovascular system. TRPV1 ion channels have
important functions as cellular sensors, and are involved in nociception, taste perception,
thermosensation, mechano‐ and osmolarity sensing, and regulation of signal transmission.15,
55, 56 In addition to ECS and physicochemical activators,15, 33, 55, 56, 57, 58 TRPV1
is activated by tetrahydrocannabinol, cannabinol, cannabigerol and some propyl homologs
of THC and cannabigerol.59, 60, 61, 62, 63, 64, 65, 66, 67 Cannabichromene (CBC),
cannabidiol, and cannabinol are strong TRPA1 agonists and desensitizers, and THCV
(from a botanical extract) is a potent regulator of TRPA1.62
The ECS in CVD Pathology
The endocannabinoid system plays a major role in the cardiovascular system, especially
in disease states. Under normal conditions in healthy animals, modulation of the ECS
has minor consequences and does not result in tonic changes.43 In disease, however,
the ECS is dysregulated, or dysregulation results in disease.68 There are reports
ranging from patient‐reported and anecdotal evidence through in vitro and in vivo
studies and some clinical/epidemiological studies that suggest modulation of the ECS
occurs during the development of CVD pathology. This, in turn, suggests a therapeutic
potential in the modulation of the ECS. Endocannabinoids and their synthetic analogs
have important effects on the cardiovascular system, including complex mechanisms
affecting the vasculature and the myocardium, but also autonomic outflow regulation
through sites of action in the central and peripheral nervous system.43, 66, 69, 70
Modulation of the ECS has been suggested as a therapeutic avenue for various disorders
of the cardiovascular system ranging from atherosclerosis and restenosis, hypertension,
cirrhotic cardiomyopathy; to myocardial infarction, and chronic heart failure.42
Myocardial Infarction (Ischemia/Reperfusion Injury)
In the myocardium in human adipose tissue of ischemic hearts, CB1 receptor expression
is upregulated, accompanied by CB2 receptor and FAAH downregulation, as well as reduced
cell survival signaling.9, 71, 72 This goes along with an increase in circulating
immune cells in obese patients with adverse cardiovascular events. Coronary dysfunction
is associated with elevated endocannabinoid plasma levels in obese people, due to
CB1 receptor upregulation, and results in cellular dysfunction and cell death in endothelial
cells and cardiomyocytes.73 The role of CB2 receptors is to decrease leukocyte infiltration
and enhance pathways that contribute to survival.9, 71, 72, 74 TRP channels account
for the sensing mechanisms of cardiac pain caused by myocardial ischemia.75 TRPV1‐positive
sensory nerves react to multiple ischemic metabolites and sequelae (substance P, Calcitonin
gene‐related peptide (CGRP), pH) and cause chest pain.33, 76, 77
Heart Failure and Cardiomyopathy
In heart failure and cardiomyopathies, expression of cardiomyocytes and endothelial
cells change; as well as the number of circulating immune cells and platelets. In
cardiomyocytes and endothelial cells CB2 receptors initiate inflammation, and CB1
receptors promote cardiac dysfunction and cell death.42
Atherosclerosis
Atherosclerosis is an inflammatory condition in which the concentration of immune
cells is elevated, and vascular smooth muscle cell expression is changed. CB2 receptors
promote monocyte chemotaxis, infiltration and activation; leading to vascular inflammation,
plaque development, and vascular smooth muscle cell proliferation.9, 71, 72, 74 Furthermore,
CB1 receptor expression in macrophages and endocannabinoid concentration of anandamide
and 2‐AG in the blood is meaningfully higher in patients with unstable angina compared
with patients with stable angina47 indicating that receptor expression, and thereby
theoretical endocannabinoid‐receptor interaction, is directly linked to disease severity
in patients with atherosclerosis. CB1 agonism reduces the blood pressure significantly
more in spontaneously hypertensive rats than in normotensive rats, and CB1 receptor
expression is higher in the heart and aortic endothelium in spontaneously hypertensive
rats compared with normotensive rats.43, 50 In addition, ∆‐9‐THC‐stimulated human
T‐cells show less proliferation and inhibition of interferon‐gamma production, as
well as downregulation of T‐helper 1 cells78 that are present in atherosclerotic lesions
and which contribute to the inflammatory state of the lesions. The endocannabinoid
system (ECS) and cannabinoid receptors (both CB1 and CB2) are highly active in cells
found in atherosclerotic plaques such as macrophages and vascular smooth muscle cells.2,
79 Macrophages are activated by oxidized LDL through increased (anandamide) and 2‐arachidonoylglycerol
(2‐AG) concentration, as well as upregulation of CB1 and CB2, thus initiating cholesterol
accumulation in immune cells, affecting endothelial cells, and vascular smooth muscle
cells.2, 79, 80
Pro‐, and Anti‐Atherogenic Effects of Cannabinoids
The active psychotropic component of marijuana (∆‐9‐THC), along with other CB1 and
CB2 ligands, have been suggested to have an anti‐atherogenic effect on coronary artery
disease. However, there are also reports that CB1 agonism is pro‐atherogenic, where
activation of CB1 results in activation of mitogen‐activated protein kinases and increased
AT1 receptor expression which elevates the concentration of reactive oxygen species,
promoting endothelial cell injury, and lipid accumulation in macrophages.81 CB1 antagonism
and CB2 agonism have been suggested to be anti‐atherogenic, where decreased Platelet‐derived
growth factor (PDGF) dependent proliferation and migration of vascular smooth muscle
cells, repressed cytokine gene expression, less macrophage recruitment (2) ∆‐9‐THC
agonism reduced levels of intracellular adhesion molecules, leading to less migration
of monocytes, decreased inflammatory response and size‐reduction of arterial plaque
and inhibited action of oxidized LDL.47, 78, 82 Finally, rimonabant, a selective CB1
antagonist used to treat obesity, reduces progression of atherosclerosis by lowering
gene expression of proinflammatory cytokines in macrophages.47 Interestingly, rimonabant
also decreases progression of CAD at a low concentration (30 mg/kg instead of 50 mg/kg)
while not affecting serum cholesterol and associated weight loss; but through decreasing
the expression and number of macrophages, and associated proinflammatory cytokines
in the aorta.83 Administration of rimonabant decreases vascular smooth muscle cell
proliferation and migration, and decreases inflammatory response in human coronary
arteries.82
Exogenous Cannabinoids and CVD: Paradoxes and Therapeutic Potential
Exogenous cannabinoids refer to cannabinoids that are obtained from the plant Cannabis
sativa (phytocannabinoids) or synthesized analogs. The most studied phytocannabinoids
include ∆‐9‐tetrahydrocannabinol (∆‐9‐THC), cannabinol, and cannabidiol.84 These compounds,
as well as native mixtures from marijuana, are the subject of intense interest due
to their therapeutic potential. Medical marijuana users report (anecdotally and outside
of the peer‐review system) effects such as stabilization of angina episodes, increased
cardiovascular well‐being and health. However, the heart‐racing effects of acute marijuana
exposure are well‐documented, specifically after smoking marijuana, where both heart
rate and left ventricular function significantly elevate for at least 1 hour. Direct
use of marijuana in humans induced an amplified risk (up to 4.8 times) for myocardial
infarction (MI) in the first hour of consumption; however, the risk rapidly declines
after 1 hour.4, 7, 85, 86 In a study that evaluated data that spanned 15 years concluded
that marijuana consumption is not independently associated with cardiovascular risk
factors.85 Nonetheless, there is a possible increased risk of mortality for patients
who have already had a past myocardial infarction compared with marijuana smokers
that did not.87 Some early studies concluded that marijuana users do not have a significantly
increased risk of stroke and heart failure later showed that those risks were significant
upon longer follow up with multivariable analysis showing greater relative risk of
myocardial infarction the younger group.3, 88 The CARDIA cohort study which spanned
25 years showed no association of marijuana use with CVD or atherosclerosis risk.5,
6 Furthermore, many studies have been inconclusive and suggest that further research
on a larger scale with repeated measures are needed.3, 4, 7 Despite the possible CVD
risks associated with marijuana use, there is rational potential for modulation of
the ECS using exogenous cannabinoids derived from plants or synthetic sources, as
single drugs or complex mixtures, for treatment of disease in the CVD space. Potential
therapeutic avenues are explored below:
Modulation of FAAH
Modulation of FAAH is one of the main gatekeepers in the control of many cardiac functions:
FAAH‐knockout mice are less susceptible to age‐associated decline in cardiac function
compared with wild‐type mice, notably without disruption to CB1‐regulated functions
like body temperature and locomotion.89 FAAH−/− mice have a higher endogenous concentration
of anandamide (and related fatty acid amides) in brain, heart, liver, and other organs.90,
91 Moreover, endocannabinoids tonically suppress contractility in hypertension. By
increasing the concentration of endogenous anandamide (by inhibition of FAAH), reduced
blood pressure, cardiac contractility, and vascular resistance can be achieved.50
Modulation of CB1
Recent studies suggest that CB1 receptors play a major role in cardiovascular regulation.
This has been implicated in ischemic preconditioning and ischemia‐reperfusion injury
of the myocardium.43, 50 CB1 receptors that are in the myocardium mediate negative
ionotropy, both in vivo and in vitro,42 making the heart less contractile. In vascular
tissues, CB1 activation results in vasodilation. Both effects are assumed to accompany
the pro‐hypotensive effect of anandamide in anesthetized rodents. Moreover, CB1 antagonism
reverses the effect in spontaneously hypertensive rats resulting in increased blood
pressure and left ventricular contractile activity. Conversely, CB1 agonism with anandamide
tonically suppresses cardiac contractility in hypertension, leading to normalized
blood pressure, reduced cardiac contractility and vascular resistance when blocking
the degradation of anandamide;50 representing a good approach for therapeutic intervention
to decrease cardiovascular risk factors such as hypertension.9
Modulation of CB2
There is experimental evidence implying CB2 receptors are involved in the progression
of atherosclerosis. The effects of oral administration of ∆‐9‐THC in a murine model
of established atherosclerosis was determined, and results showed a significant inhibition
of disease progression with increased expression of CB2 receptors on atherosclerotic
plaques in both humans and mice.92 CB2 agonism results in less proliferation capacity
of lymphoid cells and decreased interferon‐gamma secretion; as well as inhibition
of macrophage chemotaxis.92 This protective effect could be reversed by CB2 antagonist
SR144528.9
Modulation of Ionotropic Cannabinoid Receptors
Vanilloid receptors mediate the response of cardiac spinal afferent nerves after an
ischemic period and act as molecular sensors to detect myocardial and tissue ischemia
and activating cardiac nociceptors.75, 93 Pretreatment with capsaicin results in cardiac
dysfunction with increased left ventricular end‐diastolic pressure and leads to altered
expression of a variety of neuronal and non‐neuronal genes in the heart.94 TRPV1 receptors
increase SP release from capsaicin sensory neurons to protect the heart from injury,
and regulate normal cardiac function and development of cardiac adaptation to ischemic
stress.95, 96
Additionally, 12‐lipoxygenase‐derived eicosanoids are found to protect against myocardial
I/R injury by activation of TRPV1 in Langendorff rat hearts.97 A mixture of 12(S)‐HpETE
(12‐LOX arachidonic acid metabolite and endogenous ligand for TRPV1) and arachidonic
acid was used. Infarct size was reduced by 40%, an effect that could be reversed by
the 12‐LOX inhibitor baicalein, or by desensitization with capsaicin on local sensory
C‐fiber afferent nerves. HpETE and arachidonic acid both caused dose‐dependent coronary
vasodilation that was suppressed by TRPV1 antagonist capsazepine, or with a CGRP antagonist,
clearly showing the upregulation of TRPV1 during I/R injury.96, 97
In vivo, mice lacking functional TRPV1 were protected from pressure overload cardiac
hypertrophy compared with wild‐types, showing that TRPV1 may be involved in the progression
of cardiac hypertrophy.15 Recent studies also show that pre‐clinical administration
of the TRPV1 antagonist BCTC (4‐(3‐Chloro‐2‐pyridinyl)‐N‐[4‐(1,1‐dimethylethyl)phenyl]‐1‐piperazinecarboxamide)
resulted in prevention of loss of heart function in a mouse model of cardiac hypertrophy
and heart failure; indicating that TRPV1 antagonism offers novel treatment options.98
Comparison between TRPV1 KO mice and their wild‐type littermates show that the genetically
modified mice have no pain response, less swelling after subcutaneous injection with
vanilloid compounds, and an attenuated response to acidified environments or heat
(43°C). TRPV1‐/‐ mice had no reduction in body temperature after subcutaneous injection
with capsaicin, and homozygous mice show no aversion of drinking capsaicin‐supplemented
drinking water.99 Furthermore, TRPV1 knockouts are hypometabolic (less oxygen consumption),
hypervasoconstricted (lower‐tail skin temperature), preferred lower ambient temperature,
and showed a higher locomotor activity compared with wild‐types.93 Administration
of the TRPV1 endogenous agonist anandamide and exogenous agonist Resiniferatoxin (RTX)
both induced stress‐related hyperactivity in TRPV1+/+ mice, but not in TRPV1 knockouts.93
Summary: Promise and Challenges for Cannabinoid Therapeutics and CVD
Endocannabinoids and cannabinoid‐related compounds may be a promising approach as
therapeutic agents for cardiovascular diseases. However, there are several challenges
that arise when considering these targets.
Likely Side Effect Profiles of Drugs Targeting Broadly Expressed Metabotropic and
Ionotropic Cannabinoid Receptors
Putting the striking progress aside when it comes to understanding the functions of
the TRP channel family, some problems persist. TRPV1 channel ligation can be beneficial
in one organ and induce unacceptable adverse side effects in another.56 For example,
in clinical trials, small molecule TRPV1 (TRPV3 and TRPA1) antagonists were used to
treat inflammatory, neuropathic, and visceral pain, but studies were terminated because
of adverse effects induced by TRPV1 antagonists.100 Hyperthermia and impaired noxious
heat sensation placed patients at risk for scalding injury. Second generation TRP
antagonists that do not induce an increase in core body temperature has been reported,
nevertheless the therapeutic utility is not yet known.100 Administration of CB1 agonists
in vivo causes complex hemodynamic changes, including changes of heart rate as well
as increased and decreased blood pressure.101
Regulatory and Formulation Issues Arising From Use of Plant‐Derived Compounds or Native
Mixtures
Safety and efficacy of cannabis‐derived medicines are a major issue. If therapeutic
potential resides in a single molecule component or a derivative, then production
and regulation of the therapy are straightforward. If the efficacious agent is a complex
mixture that reflects some or all of the secondary metabolome complexity of C. sativa,
then safe and consistent production become challenging. In this case, controlled preparation
of synthetic mixtures is likely to be more desirable than attempting to produce native
extracts to the level of consistency required for FDA approval.
In summary, the endocannabinoid system is highly active in cardiovascular disease
states. Modulation of the ECS, CB1, and TRPV1 antagonism, as well as CB2 agonism,
have proven to modulate disease state and severity in CVD. Studies are underway to
develop drugs to change the course of cardiovascular diseases. Areas of promise include:
CB1 antagonism which has an anti‐inflammatory effect and reduces smooth muscle cell
proliferation, as well as CB2 agonism which results in decreased expression of adhesion
molecules, reduced inflammatory response, reduced plaque size in atherosclerosis and
inhibits the action of oxidized LDL. Of particular interest is the fact that TRPV1
antagonism protects the heart from heart failure‐associated remodeling, especially
given the plethora of available TRPV1 antagonists tested in Phase II clinical trials
for pain, and other indications.
Further research and clinical trials are necessary to develop a safe agonists and
antagonists for the treatment of cardiovascular diseases, and ligands for CB1, CB2
and TRPV1 that are found in cannabis may yet play a role in either guiding rational
design, the demonstration of effective systems to target, or as single or combinatorial
therapies in their own rights.
Sources of Funding
Support for this work was provided by funding from the National Institutes of Health,
National Institute of General Medical Sciences COBRE P20GM113134; the Hawaii Community
Foundation, Medical Research Grant #16CON‐78925.
Disclosures
Dr Stokes is founder of Makai Biotechnology, LLC, a cardiovascular disease‐focused
biotechnology company. Dr Turner is a member of the scientific advisory board of GBSciences,
Inc, and receives research funding from GBSciences, Inc, at the time of submission.
Dr Small‐Howard is employed by GBSciences, Inc. The remaining authors have no disclosures
to report. No sponsor‐exerted editorial influence was involved in the development
of the manuscript.