Role of the endocannabinoid system in homeostasis and adaptation to pathological conditions in the cardiopulmonary system
Zusammenfassung der Projektergebnisse
In the project “Role of the endocannabinoid system in homeostasis and adaptation to pathological conditions in the cardiopulmonary system” we investigated the function of endocannabinoids in the regulation of pulmonary blood pressure in health and disease as well as in myocardial and vascular remodeling. We found that the endocannabinoid anandamide (AEA) is a critical mediator of hypoxic pulmonary vasoconstriction, which is a key physiological adaptation process in the lung. The underlying molecular mechanisms have not been entirely clarified so far. Our experiments now illustrate that hypoxia enhances the levels of AEA in pulmonary arterial smooth muscle cells, where AEA is metabolized by the enzyme fatty acid amide hydrolase (FAAH) to eicosanoids such as leukotrienes causing pulmonary vasoconstriction. We also demonstrate in mice that the AEA/FAAH axis is involved in the generation of pulmonary hypertension (PH). This is a devastating disorder characterized by high pulmonary blood pressure, inflammation and remodeling of the intrapulmonary vessels that can lead to death within few years, when untreated. Inhibition of the FAAH enzyme proved to prevent the development of PH in a hypoxia-induced mouse model of PH. Our experiments suggest that this effect is not related to the lack of FAAH-dependent eicosanoids but rather due to accumulation of AEA that acts via cannabinoid 2 (CB2) receptors inhibiting smooth muscle growth, pulmonary inflammation and remodeling. These results have in part already been published in the Journal Proceedings of the National Academy of Sciences (PNAS) and have been awarded by the René Baumgart Foundation in 2014. Moreover, they were distributed to the public by a press release of the University of Bonn. Besides the important function of endocannabinoids in adaptation to hypoxia in the lung, we also revealed a critical role for the endocannabinoid receptor CB2 in cardioprotection of the ischemic myocardium. In a mouse model we have described mechanisms of the endocannabinoid-CB2 receptor axis-mediated prevention of cardiomyocyte apoptosis including modulation of contractile elements and antioxidative enzymes. Our data revealed specific factors involved in CB2 receptor-dependent modulation of the inflammatory response and macrophage function in ischemic myocardium. 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. We explored cellular interactions and found a crucial role for CB2 receptor-dependent modulation of macrophages during their interaction with cardiomyocytes in order to prevent loss of myocardial substance and function. Our study of human hypertrophic myocardium showed activation of the endocannabinoid system associated with a subtle inflammatory reaction. We also investigated development of murine myocardial hypertrophy and found involvement of similar CB2 receptor-mediated mechanisms including adaptation of contractile elements and antioxidative enzymes for prevention of cardiomyocyte apoptosis. Taken together, our findings provide evidence for model-independent, systemic CB2 receptor-associated mechanisms of cardioprotection and adaptation. In addition, we described involvement of the endocannabinoid system in human aortic aneurysms. We expect that these studies not only provide novel mechanistic insights into cannabinoid-mediated modulation of cardiopulmonary function under healthy and pathological conditions, but also open perspectives for future studies and exploration of the therapeutic potential of this system.
Projektbezogene Publikationen (Auswahl)
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Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L-826,266. Naunyn-Schmied Arch Pharmacol. 2010;381:21-31
Günther J, Schulte K, Wenzel D, Malinowska B, Schlicker E
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Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci USA. 2013; 110(46):18710-5
Wenzel D, Matthey M, Bindila L, Lerner R, Lutz B, Zimmer A, Fleischmann BK
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Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis. Life Sciences. 2013;92:976-983
Duerr GD, Heinemann JC, Dunkel S, Zimmer A, Lutz B, Lerner R, Roell W, Mellert F, Probst C, Esmailzadeh B, Welz A, Dewald O
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The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy. Basic Research in Cardiology. 2014;109:425
Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, Tiemann K, Alferink J, Burgdorf S, Buchalla R, Zimmer A, Lutz B, Welz A, Fleischmann BK, Dewald O
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Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm. BioMed Research International. 2015;2015:456582
Gestrich C, Duerr GD, Heinemann JC, Meertz A, Probst C, Roell W, Schiller W, Zimmer A, Bindila L, Lutz B, Welz A, Dewald O
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CB2 receptor-mediated effects of pro-inflammatory macrophages influence survival of cardiomyocytes. Life Sciences. 2015:138:18-28
Heinemann JC, Duerr GD, Keppel K, Breitbach M, Fleischmann BK, Zimmer A, Wehner S, Welz A, Dewald O
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Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice. Life Sciences. 2015; 138:8-17
Duerr GD, Heinemann JC, Gestrich C, Heuft T, Klaas T, Keppel K, Roell W, Klein A, Zimmer A, Velten M, Kilic A, Bindila L, Lutz B, Dewald O
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The role of endocannabinoids in injury and adaptation. Life Sciences. 2015;138:1-2
Dewald O, Zimmer A
