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

急性心肌梗死(MI)是世界范围内主要的死亡原因。鉴于公共卫生系统的高死亡人数和相关成本，更好地了解心肌梗死愈合的过程至关重要。心肌梗死后的第一阶段是急性炎症反应，特征是白细胞，主要是中性粒细胞和单核细胞，渗入梗死心肌。随后，中性粒细胞和死亡的心肌细胞被巨噬细胞吞噬，从而导致炎症的消退。在随后的增殖期，激活的巨噬细胞释放细胞因子和生长因子，从而诱导新的血管生成(由内皮细胞驱动)，并由肌成纤维细胞产生细胞外基质。这会导致肉芽组织的形成。成熟期包括微血管内皮细胞和肌成纤维细胞的凋亡和稳定的瘢痕形成。这种良好调节的修复过程的紊乱导致心功能恶化，最终可能导致心力衰竭。目前尚不清楚内源性大麻素是如何影响心肌梗死后白细胞的动员、募集和激活的，我们希望以系统的方法进行研究(目标1)。我们的第二个目标是揭示内源性大麻素水平的昼夜波动、白细胞募集和梗塞愈合质量之间的可能关系(目标2)。已经描述了急性炎症中白细胞募集的昼夜振荡，在小鼠的黑暗期(=活动期)开始时迁移率最高。这也是观察到内源性大麻素水平最高的时候。因此，我们提出了临床上相关的问题，是否一天中的时间决定了心肌梗死愈合的质量，以及这是否由于内源性大麻素水平的昼夜变化所致。我们的发现有望揭示新的治疗靶点，以改善心肌梗死后的愈合，从而改善心功能。

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.