Results from different studies showing CB2 receptor-associated cardioprotective action are still fairly controversial and no single specific mechanism could be identified. Several groups investigated the involvement of the endocannabinoid system in cellular systems and function of cardiomyocytes, fibroblasts, macrophages and endothelial cells. While some studies are limited in their translational relevance, a few recent studies describe a myocardial ischemia and reperfusion scenario in a fashion comparable to the clinical situation. Recent studies provided evidence for involvement of the CB2 receptor–endocannabinoid axis in prevention of cardiomyocyte apoptosis including modulation of antioxidative enzymes and contractile elements expression. CB2 receptor has further been shown to specifically modulate the inflammatory response and macrophage function after myocardial ischemia. These effects have an impact on the subsequent myocardial remodeling, where the CB2 receptor modulates function of myofibroblasts, collagen production and limitation of myocardial infarction size. Recent experimental and clinical data showed the association of the endocannabinoid system in myocardial hypertrophy. In conclusion, increasing amount of evidence supports a crucial role of the endocannabinoid system in cardioprotection and myocardial remodeling, while some of them even suggest model-independent systemic effects in adaptation of cardiomyocytes or components of the extracellular matrix.
- myocardial ischemia
Cannabinoids have been described as potent regulators of a variety of neurological functions influencing pain control, behaviour and memory. The discovery of the cannabinoid receptors CB1 and CB2 led to initial description of CB1 receptor to be restricted to neurons while CB2 receptor was found on immunological cells. Later studies reported these receptors being also localized on vascular cells  and in the heart . Furthermore, production of ligands to the cannabinoid receptors—endogenous cannabinoids—was reported in endothelial cells . Experiments performed
2. Mechanisms of cardioprotection
Myocardial protection is a very complex system involving not only intracellular mechanisms in cardiomyocytes, but also bearing a large contribution of cells within the local microenvironment in the heart. The contradictions in the experimental evidence for specific mechanisms in the cardiomyocytes are not only related to differences in experimental setup, but also most probably associated to variations in mediators and cells within the local microenvironment. These factors make it difficult to draw clear conclusions from experimental data which will lead to new targets for therapy. Therefore, significant efforts have been made to enlighten the complexity of cardioprotection.
A number of signalling cascades and systems are involved in cardioprotection. Based on strong experimental and clinical evidence, the first line of intervention is aiming at the earliest possible restoration of the blood flow, i.e., reperfusion. The very early observation of timely onset of reperfusion leading to preservation of myocardial function [5, 6] provided ground for the clinical introduction of early percutaneous coronary intervention. Subsequently, Murry introduced the concept of ischemic preconditioning based upon four episodes of five minutes ischemia interrupted by each five minutes of reperfusion before a myocardial infarction was induced (40 minutes ischemia) and thereby resulting in decreased infarct size . Interestingly, this effect was not found after a three-hour ischemia period underlining the ultimate goal of early reperfusion. This concept of myocardial conditioning was first applied in temporal relation to the myocardial injury, thereby defining preconditioning and postconditioning . Studies extended this concept by introduction of spatial component in remote preconditioning, where short, repetitive limb occlusions provide protection to the following longer episode of myocardial ischemia [9, 10]. The latter concept was clinically implemented and proved to be beneficial to the patients . Numerous studies described a wide range of molecules and signalling cascades involved utilizing different models, species, and pharmacological or genetic manipulation. So far there are only scattered reports investigating the role of endocannabinoids in ischemic preconditioning. One of the studies applied heat stress preconditioning 24 hours before isolation of the hearts, which then underwent 30 min ischemia and 120 minutes reperfusion
Another important area of cardioprotection originated in studies describing effects of modulation of inflammatory response during reperfusion injury. The very early studies reported detrimental outcome in patients treated with methylprednisolone after reperfusion of myocardial infarction . Despite this drawback, it was the experimental work in subsequent years which provided solid evidence for beneficial effects of reperfusion . The effects of inflammation in reperfusion must also be differentiated in a temporal and spatial context, because reperfusion initially induces a strong inflammatory response. In short-term (few days), this leads to a stronger functional impairment of the heart than without reperfusion, but the long-term effects of reperfusion have been proven to preserve the myocardial function and could even prevent development of dysfunction. The ischemia of myocardial tissue leads to accumulation of free radicals and toxic metabolic products while the adenosine triphosphate storages are depleted and cellular homeostasis is increasingly impaired. The reperfusion of ischemic myocardium is associated with activation of the complement system and a strong increase in reactive oxygen species (ROS). The subsequent response includes activation of tumour necrosis factor α (
Differentiation of monocytes to macrophages in myocardium leads to even further increased production of inflammatory cytokines, while macrophages initiate their production of growth factors, e.g., basic fibroblast growth factor or vascular endothelial growth factor. As a result, proliferation of fibroblasts, differentiation of myofibroblasts and neoangiogenesis are initiated and all aiming at granulation tissue formation and tissue remodeling. These events involve different macrophage subpopulations, which are differentiated upon polarization of the lymphocytes response from
Among other factors, specific chemokines have been associated with modulation of macrophage function. Chemokines are a subgroup of cytokines having distinct effects on mononuclear cells and macrophages, but also on neutrophils and endothelial cells. One of the most potent monocyte chemoattractants is the chemokine
3. Experimental evidence for involvement of endocannabinoids in cardioprotection
One of the first publications reported a CB1 receptor-mediated decrease in contractility of human atrial muscle . Cannabinoids also led to a reduction of left ventricular systolic pressure . There is a certain variability in results between
Application of a non-specific (acting on CB1 and CB2 receptor) agonist WIN55212-2 was shown to reduce infarct size in a mouse model of coronary occlusion without reperfusion, while it decreased myeloperoxidase activity of neutrophils . CB2 receptor can influence the
Recent work from our group investigated the role of endocannabinoids and CB2 receptor in a mouse model of non-infarcted ischemic cardiomyopathy induced by brief repetitive I/R. Repetitive daily episode of 15 minute ischemia followed by reperfusion until the next day lead to a transient inflammatory reaction, development of interstitial fibrosis and left ventricular dysfunction . We could show that fibrosis and dysfunction are reversible after 60 days of recovery after the last episode of I/R, where normal left ventricular myocardium is found. This is of clinical interest since: (a) repetitive episodes of ischemia are the hallmark of angina pectoris in patients and (b) these functional and morphological characteristics are also found in human hibernating myocardium with restoration of normal function after revascularization . Mice with overexpression of SOD showed significantly less inflammation and fibrotic depositions associated with almost normal left ventricular function in this model and thereby revealed the importance of ROS in development of fibrosis and left ventricular dysfunction . Another study in the same mouse model revealed a crucial role for the chemokine
The consequences of prolonged inflammatory response were not limited to cardiomyocyte loss, but also involved adverse remodeling process in
Based on these findings we utilized
In summary, our
4. Endocannabinoids in cellular mechanisms of myocardial adaptation
Several studies investigated the effects of cannabinoid receptors in regulation of cellular homeostasis and pathology, but their methodological differences and model-related problems do not allow to drawn clear and direct conclusions. A number of pharmacological studies investigated the impact of cannabinoid receptors on blood pressure
Potential cardioprotective effects were described for cannabidiol based on the lower incidence of arrhythmia in rat hearts after ischemia and reperfusion, but the authors only speculated about involvement of cardiac current and channels . The already above mentioned study suggested CB2 receptor-related cardioprotection after hydrogen peroxide treatment leading to increased apoptosis of cardiomyocytes and higher differentiation potential of myofibroblasts
Based on our data from cardiomyocytes
5. Clinical perspective for endocannabinoids in myocardial adaptation
A number of clinical studies described the involvement of endocannabinoids in human cardiac conditions. One study described an increased level of endocannabinoids in the blood stream and higher expression of CB2 receptor in the heart of patients with terminal heart failure . Another study from the same group described significant reduction of plasma anandamide concentration after induction of general anaesthesia using isoflurane . In the same patient population they reported a significant increase in 2-AG after onset of cardiopulmonary bypass during heart surgery, but remained only speculative on the clinical relevance of these findings by suggesting association with inflammatory response. A recent study from our group showed activation of the endocannabinoid system and up regulation of its receptors in myocardial hypertrophy in patients with aortic valve stenosis . We were able to identify expression of CB2 receptor predominantly on cardiomyocytes, but also on myofibroblasts and mononuclear cells in hypertrophic myocardium. The same study revealed a persistent low-grade inflammation and active remodeling in hypertrophied hearts and this shows parallels to our experimental findings discussed above.
The endocannabinoid system gained clinical relevance in the last few years because of a CB1-receptor antagonist based therapy (rimonabant) being approved for clinical use in severely obese patients, but then disappeared rather early due to unwanted and detrimental side effects . Still, one study investigated the effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease (STRADIVARIUS randomized controlled trial). The results were disappointing for the primary endpoint, since no effect could be identified on the disease progression . Still, the secondary endpoint of normalized total atheroma volume was met and this could be the basis for future studies. In the light of our results on the role of the chemokine
Growing amount of evidence supports the role of the endocannabinoid system and cannabinoid receptors in cardioprotection and myocardial adaptation. Several mechanisms have been described in specific cells
OD was supported by DFG FOR926 grants DE802/2-1 and 2-2. GDD was supported by a BONFOR grant from the Medical School, University of Bonn, Germany.
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