Abstract
Endocannabinoids exert their actions in the heart and vessels, at least in part, by stimulating the cannabinoid CB1 and the CB2 receptor subtypes which belong to a group of seven transmembrane-spanning receptors and are coupled to Gi/o-proteins. Activation of cardiovascular CB1 receptors leads to depressed cardiac contractility and hypotension. Conversely, in most studies, the CB1 receptor antagonists are cardioprotective against ischemia–reperfusion injury, myocardial ischemia, heart failure, and cardiomyopathies. Evidence to date indicates that CB2 receptor activation is cardioprotective. CB2 receptor-mediated effects such as anti-inflammation and anti-fibrosis may be in part opposite to the actions of the CB1 receptor. The aim of this review is to up-date on recent experimental findings and controversies on the role of endocannabinoid system in the myocardial injury with emphasis on pathophysiological processes such as left ventricular remodeling, cardiac fibrosis, hypertrophy, and endothelial dysfunction. Recent experimental studies employing genetic deficiency of CB1 and CB2 receptors and endocannabinoid anandamide metabolizing enzymes are reviewed. Moreover, the protective mechanisms which are mediated by cannabinoid receptors during ischemic preconditioning as well as in the early and late phase after myocardial infarction are discussed in the context of possible therapeutic implications.
Keywords
- cannabinoid receptors
- CB1
- CB2
- heart
- myocardial infarction
- heart remodeling
1. Introduction
Endocannabinoids, its degrading enzymes and the cannabinoid CB1 and CB2 receptors are present in rodent and human cardiovascular tissues. In addition to its role in the control of the central nervous system, the endocannabinoid system (ECS) may play a pivotal part in cardiovascular regulation by heart diseases (reviewed in [1-3]).
In normal physiological conditions, ECS is not highly regulated. However, by cardiovascular pathologies, this system is activated and may reflect a protective response which limits cardiac injury. Activated ECS has been implicated in acute cardiovascular conditions such as hemorrhagic, septic, and cardiogenic shock as well as in chronic diseases such as coronary heart disease, heart failure, and cardiomyopathy.
Endocannabinoids exert their actions in the heart and vessels, at least in part, by stimulating the cannabinoid CB1 and the CB2 receptor subtypes which belong to a group of seven transmembrane-spanning receptors and are coupled to Gi/o-proteins [4, 5]. Signaling through the CB1 receptor elicits hypotension, bradycardia, and negative inotropy [6]. Moreover, this receptor subtype is implicated in inflammation, apoptosis, oxidative stress [7], and metabolic dysregulation [8], thereby contributing to tissue injury. The CB2 receptors, on the contrary, may play a compensatory anti-inflammatory, anti-oxidative, and anti-atherogenic role [9, 10] contributing to cardiovascular protection.
Nevertheless, the role of cannabinoid receptors in the heart under several pathological conditions remains controversial. Recent studies on hemodynamic, antiarrhythmic, and cardiometabolic effects of cannabinoids have been highlighted in several excellent reviews [2, 3, 11-14]. Hence, these topics are not in the scope of this chapter.
The aim of this review was to up-date on recent findings and controversies on the role of ECS in the myocardial injury with emphasis on pathophysiological processes such as left ventricular remodeling, cardiac fibrosis, hypertrophy, and endothelial dysfunction. Starting with the localization of the cannabinoid system components in the heart under normal and pathological conditions, the role of both CB1/CB2 receptors in the regulation of the cardiac function will be analyzed. Experimental studies in mice deficient in cannabinoid receptors and endocannabinoid anandamide metabolizing enzymes greatly expanded our knowledge on the role of ECS. Hence, lessons from these studies will also be discussed. Moreover, the protective mechanisms which are mediated by cannabinoid receptors during ischemic preconditioning as well as in the early and late phase after myocardial infarction will be described in the context of possible therapeutic implications.
2. Endocannabinoids and cannabinoid receptors in the heart
The major endocannabinoids, anandamide, and 2-arachidonoylglycerol (2-AG) have been detected in the rat heart by Schmid et al. [15]. These findings were later confirmed by Wagner et al. [16] who also revealed the presence of CB1 receptors via immunohistochemistry in isolated rat hearts. Finally, the presence of both CB1 and CB2 receptors has been confirmed in myocardium of rat [17, 18], mice [19], and guinea pigs [20]. Messenger RNA and immunoreactivity for CB1 receptors have also been reported from murine cardiomyocytes [21], and only one receptor subtype, CB1, was present on neonatal cardiomyocytes [22].
In human heart, CB1 mRNA expression has been first found by Galiegue et al. [23] and later confirmed in isolated human atrial muscle on the protein level by Bonz et al. [24]. Moreover, human primary cardiomyocytes [9] and coronary vascular smooth muscle [25] also expressed CB1 receptors. Finally, it has been recently demonstrated that mRNA transcripts of CB1 and CB2 receptors are expressed in an almost equal proportion on healthy human left ventricular myocardium [26].
Hence, the main components of the ECS are present in rodent and human healthy heart. Their regulation under pathophysiological conditions has been intensively investigated during the last decade in different models of cardiac injury and in human diseases.
To begin with, circulating levels of endocannabinoids were elevated after cardiac injury, such as
Interestingly, in
In humans, the endocannabinoid 2-AG level elevated in the infarct-side coronary artery of
Recently, in
Concerning intracellular localization of the cannabinoid receptors, evidence is now provided for CB1 receptors. They were found in specific restricted regions within cardiac myocytes as demonstrated by array tomography in mice heart tissues [35]. Moreover, Currie et al. [36] suggested the existence of cardiac nuclear CB receptors.
Altogether, endocannabinoids and both CB1/CB2 receptors are present in human and murine hearts. The receptors co-localize with cardiac myocytes, coronary vascular smooth muscle, and endothelial cells as well as with epicardial adipose tissues.
Increased circulating and myocardial endocannabinoids levels as well as regulation of CB1 and CB2 receptors in heart diseases may reflect a protective response of the local ECS to limit cardiac injury. Whereas the CB1 receptors expression levels are controversially regulated depending on the heart disease model and cardiac function, the CB2 receptors are mostly upregulated. Thus, the endocannabinoid—CB2 receptor protective axis may play a major role in limiting injury.
3. Cardiac function
In healthy individuals, activation of ECS does not significantly regulate cardiac functions. In the intact heart of rodents, endogenous CB1/CB2 receptor agonists are also not involved in the electrophysiological processes and cardiac rhythm regulation [37]. Conversely, CB1 receptor antagonists do not affect cardiac hemodynamic in normotensive rodents [6, 30].
As previously described, in cardiac disorders and after myocardial infarction, circulating levels of endocannabinoids are elevated and the majority of studies suggest that this elevation improves cardiac performance [3, 27].
However, administration of anandamide, D9-tetrahydrocannabinol (
Regulation of cardiac contractility by the cannabinoid system is complex and includes actions on the nervous system and local cardiac mechanisms.
It has been previously assumed that cardiovascular effects of cannabinoids were centrally mediated through activation of receptors in the brain. However, evidence from studies mentioned below suggests that most effects are mediated locally through cardiac cannabinoid receptors. The activation of presynaptic CB1 receptors might decrease the release of noradrenalin contributing to negative inotropy [41]. Albeit, in some studies, effects on cardiac contractility were independent of the endogenous noradrenalin release [42]. Other possible mechanisms of negative inotropic effects include inhibition of voltage-dependent Na+ and L-type Ca2+ channels in myocytes [43] and suppression of Na+/Ca2+ exchanger current [44, 45].
It is now becoming clear that negative inotropy is mediated through the CB1 receptor. This has been shown in papillary muscles, isolated hearts, and in rodent
In contrast to CB1 receptor activation, CB2 receptor activation does not modulate the ion channel function (reviewed in [46]). Hence, it is not pronounced that the CB2 receptor mediates contractility effects. However, in one study, CB2 receptors developed positive contractile response in rat isolated atria associated with increased
Given that endocannabinoids are cleaved by hydrolysis as well as cycloxygenase-2, lipoxygenases, and cytochrom P450-mediated oxidative metabolism, the generated autacoids may exert additional cardiovascular effects [6]. This fact requires further investigations.
4. Lessons from knockout mice
4.1. CB1 receptor knockout mice (CB1 −/−)
The generation of mice deficient in CB1 or CB2 receptors has greatly expanded our knowledge on the role of these receptor subtypes in heart disease.
In
On the other hand, genetic deletion of the CB1 receptor attenuated the diabetes-induced cardiac dysfunction [31]. Moreover, this study suggests that over-activation of this receptor subtype may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating angiotensin AT1 receptor signaling,
In summary, there are controversies concerning the role of the CB1 receptor activation in cardiac pathology: It may be both deleterious and beneficial depending on the disease model. By over-activation of this receptor, the pathological reactions may be provoked.
4.2. CB2 receptor knockout mice (CB2 −/−)
In the
The role of the CB2 receptor during the initial phase of
Further studies of remodeling processes in reperfused infarction in the
Hence, it seems that the CB2 receptor is implicated in multiple pathophysiological processes after heart injury: It modulates inflammatory response, collagen deposition, and organization of stable scar during remodeling.
4.3. Fatty acid amide hydrolase knockout mice (FAAH −/− )
Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase (
However, in the doxorubicin model of heart failure,
5. Ischemia–reperfusion injury
Short ischemia/reperfusion episodes—known as ischemic preconditioning—protect the myocardium against infarction [58]. This endogenous cardioprotective mechanism could be experimentally activated at two time points: The early preconditioning when the treatment is applied 1–4 h before ischemia and the delayed preconditioning when the treatment is applied 24–72 h before induction of myocardial infarction. Importantly, endogenous cannabinoid 2-AG is increased by preconditioning in the heart [59].
Initial studies on the role of cannabinoids in cardiac ischemia were predominantly performed
Further studies, which aimed to elucidate the role of CB1/2 receptors in the heart, were performed in the animal model of myocardial infarction via ligation of the left coronary artery. Most investigations used an indirect approach by blocking the beneficial effects of endocannabinoids activation either by CB1 or CB2 receptor antagonists.
In the rat model of coronary occlusion/reperfusion, both anandamide and non-selective CB1/CB2 receptors agonist HU-210 decreased the incidence of ventricular arrhythmias and reduced infarct size through the activation of the CB2 but not the CB1 receptors [67]. Also in mouse myocardial ischemia/reperfusion model, the protective effect of a CB1/CB2 receptors agonist WIN55212-2 was abolished by the selective CB2 antagonist AM630 and not affected by the selective CB1 antagonist AM251 [68]. In this study, cardioprotection was associated with a decreased
Direct CB2 receptor activation by selective agonist JWH-133 during heart ischemia also reduced the infarct size [70] and prevented apoptosis through inhibition of the intrinsic mitochondria-mediated apoptotic pathway and involvement of the
Recently, Waldman et al. [72] observed a specific effect of non-selective activation of CB1/CB2 receptors by
Summarizing, during early and delayed ischemic preconditioning, cannabinoids activate long-lasting protective mechanisms in the heart predominantly via the CB2 receptors. The cellular mechanisms, by which endocannabinoids have a protective function by ischemia/reperfusion, include anti-apoptosis [71], prevention of inflammation [68, 72], induction of the heat shock protein 72 as well as prevention of calcium overload, and oxidative stress (reviewed in [13]).
6. Myocardial infarction and left ventricular remodeling
Acute phase post-myocardial infarction is characterized by cell death and inflammatory response, whereas in the late phase post infarction, collagen deposition, interstitial fibrosis, and extracellular matrix degradation contribute to cardiac remodeling processes [73]. Pathological left ventricular remodeling leads to progressive left ventricular dilatation and dysfunction, cardiac fibrosis, and the development of heart failure. Recent data provide evidence that cannabinoids might modulate many of these pathological processes, although the direct role of receptor subtype and interaction mechanisms is not clearly defined.
Administration of CB1 selective antagonist AM251 for 12 weeks promoted
On the other hand, recent studies suggest that the blockade of the CB1 receptor may be protective. For example, chronic treatment with the CB1 receptor antagonist rimonabant reduced infarct size in wild-type mice but not in CB1−/− mice in acute ischemia/reperfusion injury. Importantly, the protective effects were independent from weight reduction and adiponectin levels [74].
Our group described the protective effects of the CB1 receptor antagonist rimonabant on cardiac remodeling in a rat model of myocardial infarction and in metabolic syndrome [30]. Pretreatment with rimonabant prevented left ventricular dilatation and cardiac dysfunction in the early and late phase after myocardial infarction. This was evidenced by an improvement of functional cardiac parameters such as left ventricular internal diameter, ejection fraction, fractional shortening and dP/dtmax, dP/dtmin [30]. Moreover, rimonabant prevented electrocardiographic abnormalities and elevation of serum
Left ventricular remodeling post-myocardial infarction is also associated with
The late phase post-myocardial infarction is characterized by
Furthermore,
As mentioned above in
7. Conclusion
Endocannabinoids exert their actions in the heart mostly via the stimulation of the CB1 and the CB2 receptors. These receptors modulate pathophysiological processes following myocardial injury such as left ventricular remodeling, cardiac fibrosis, hypertrophy, and endothelial dysfunction.
Activation of cardiovascular CB1 receptors leads to depressed cardiac contractility and hypotension. Conversely, in most studies, the CB1 receptor antagonists are cardioprotective against ischemia–reperfusion injury, myocardial ischemia, heart failure, arrhythmias, and cardiomyopathies. The CB1 receptor antagonists also exert beneficial anti-apoptotic, anti-inflammatory, and anti-oxidative actions which are beyond inhibition of CB1-mediated negative inotropic effect.
Evidence to date indicates that CB2 receptor activation is cardioprotective. CB2 receptor-mediated effects such as anti-inflammation and anti-fibrosis may be in part opposite to the actions of the CB1 receptor. Given that tissue endocannabinoids levels are increased by cardiac injury, the protective role of CB1 inhibition may be partly explained by the activation of unopposed CB2 receptors. This fact requires further investigations. Moreover, little is known about the interaction of the CB1/CB2 receptors with other receptors like angiotensin-II receptors or PPARs as well as the role of new discovered putative endothelial cannabinoid receptor CBe and endocannabinoid metabolic products in cardiac diseases.
The endocannabinoid system indeed could represent a novel pharmacological target in treatment of cardiac disease. However, therapeutic use of cannabinoids, their synthetic analogs and cannabinoid receptor agonists/antagonists remain limited due to their psychotropic adverse effects. Therefore, it is necessary to develop newer compounds without actions on central nervous system.
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