Role of endocannabinoid system and circadian rhythm in post-myocardial infarction healing
Final Report Abstract
Myocardial infarction (MI) causes a massive loss of cardiac tissue, which induces an inflammatory response that initiates cardiac repair processes. Innate immune cells are recruited to the heart and promote the clearance of dead cardiomyocytes. This is essential for MI healing, since insufficient clearance of dead cardiomyocytes promotes unresolved inflammation and unfavorable cardiac remodeling, which may result in heart failure. In this context, we have identified a new role for neutrophils in post-MI healing, which has been largely neglected so far. Their contribution in the acute inflammatory phase after MI is generally considered detrimental. However, in acute inflammation, neutrophils are not only vital for the clearance of pathogens or debris, but also for the resolution of inflammation and return to tissue homeostasis. The incidence of cardiovascular events, such as myocardial infarction, exhibits time-of-day dependency in humans, peaking around the sleep-to-wake transition period. In addition to the increased prevalence of MI in the morning, experimental and clinical evidence suggests that the outcome after MI exhibits a similar time-of-day dependency (referred to as “circadian rhythm”). Circadian rhythms are biological processes displaying endogenous oscillations of about 24-h and are known to play crucial role in physiology. We found that the heart represents an immunologically dynamic organ with circadian fluctuations of adhesion molecule and chemokine expression and recruited leukocytes. Myocardial infarction at the beginning of the active phase resulted in significantly higher cardiac neutrophil and monocyte infiltration. We identified that circadian oscillations of chemokine receptors on myeloid cells were mediating the time-of-day-dependent extend of leukocyte recruitment into the myocardium. Consequently, an ischemic event occurring during the active phase resulted in an exaggerated inflammation and worsened cardiac repair. In a separate study, we found that the murine pericardial adipose tissue, which contains a high density of lymphoid clusters, is a relevant site for lymphocyte proliferation after MI and affects cardiac fibrosis. Moreover, we found that the cannabinoid receptor CB2 not only controls the positioning of B cells in lymphoid organs, but also regulates the proliferation of hematopoietic stem cells and progenitors in the bone marrow. Our latest published findings further highlight a relevant role for endocannabinoid lipid signalling in regulating bone marrow leukocyte mobilization. We found that the endogenous lipid ligand 2-arachidonoylglycerol (2-AG) promotes leukocyte release into the circulation and promotes cardiac leukocyte recruitment after ischemia. MI leads to enhanced circulating 2-AG levels, due to a modulation of endocannabinoid 2-AG biosynthesis and breakdown enzymes in the bone marrow and myocardium after MI.
Publications
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(2016). The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. EMBO Molecular Medicine, 8(8):937-48
Schloss MJ, Horckmans M, Nitz K, Duchene J, Drechsler M, Bidzhekov K, Scheiermann C, Weber C, Soehnlein O, Steffens S
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(2017). Ly6Chigh monocytes oscillate in the heart during homeostasis and after myocardial infarction. Arteriosclerosis, Thrombosis and Vascular Biology, 37(9):1640-1645
Schloss MJ; Hilby M, Nitz K, Guillamat Prats R, Ferraro B, Leoni G, Soehnlein O, Kessler T, Horckmans M, Luckow B, Weber C, Duchene J, Steffens S
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(2017). Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. European Heart Journal, 38(3):187-197
Horckmans M, Ring L, Duchene J, Santovito D, Schloss MJ, Drechsler M, Weber C, Soehnlein O, Steffens S
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(2018). Pericardial adipose tissue regulates granulopoiesis, fibrosis and cardiac function after myocardial infarction. Circulation 137(9):948-960
Horckmans M, Bianchini M, Santovito D, Megens RTA, Springael JY, Negri I, Vacca M, Eusanio M, Moschetta A, Weber C, Duchene J, Steffens S
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(2019). 2-arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction. Cardiovascular Research. 115(3):602-613
Schloss MJ, Horckmans M, Guillamat-Prats R, Hering D, Lauer E, Lenglet S, Weber C, Thomas A, Steffens S
