Role of endocannabinoid system and circadian rhythm in post-myocardial infarction healing

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Acute myocardial infarction (MI) is the leading cause of death worldwide. Given the high number of deaths and related costs for the public health system, it is of crucial importance to better understand the process of myocardial infarct healing. The first phase after MI is an acute inflammatory response, characterized by infiltration of leukocytes, mainly neutrophils and monocytes, into the infarcted myocardium. Subsequently, neutrophils and dead cardiomyocytes are engulfed by macrophages, thereby leading to resolution of inflammation. In the following proliferative phase, activated macrophages release cytokines and growth factors, thereby inducing neoangiogenesis (driven by endothelial cells) and production of extracellular matrix by myofibroblasts. This leads to granulation tissue formation. The maturation phase involves apoptosis of microvascular endothelial cells and myofibroblasts and formation of a stable scar. A disturbance of this well-regulated healing process leads to a worsening of cardiac function which may ultimately result in heart failure.It is unclear how endocannnabinoids influence the mobilization, recruitment and activation of leukocytes after myocardial infarction, which we want to investigate in a systematic approach (aim 1). Our second aim is to unveil a possible relationship between circadian oscillations of endocannabinoid levels, leukocyte recruitment and quality of infarct healing (aim 2). Circadian oscillations of leukocyte recruitment in acute inflammation have been described, with highest migration rates in the beginning of the dark phase (=active phase) in mice. This is also when peak levels of endocannabinoids are observed. Therefore we ask the clinically relevant question whether time of day determines the quality of myocardial infarction healing and whether this is due to circadian changes in endocannabinoid levels. Our findings will hopefully reveal new therapeutic targets in order to improve post-myocardial infarction healing and thus cardiac function.