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

内源性大麻素系统和昼夜节律在心肌梗死后愈合中的作用

• 批准号: 281673139
• 负责人: Professorin Dr. Sabine Steffens
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin I: Kardiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/281673139?language=en
• 关键词: Role; endocannabinoid; system; circadian; rhythm

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.

急性心肌梗死（MI）是全球范围内的主要死亡原因。鉴于公共卫生系统的高死亡率和相关成本，更好地了解心肌梗死愈合过程至关重要。MI后的第一阶段是急性炎症反应，其特征在于白细胞（主要是中性粒细胞和单核细胞）浸润到梗死心肌中。随后，嗜中性粒细胞和死亡的心肌细胞被巨噬细胞吞噬，从而导致炎症消退。在随后的增殖阶段，活化的巨噬细胞释放细胞因子和生长因子，从而诱导新血管生成（由内皮细胞驱动）和肌成纤维细胞产生细胞外基质。这导致肉芽组织形成。成熟阶段涉及微血管内皮细胞和肌成纤维细胞的凋亡以及稳定瘢痕的形成。这种良好调节的愈合过程的干扰导致心脏功能的恶化，最终可能导致心力衰竭。目前还不清楚内皮cannabinoids如何影响心肌梗死后白细胞的动员，募集和激活，我们希望在系统的方法中进行调查（目的1）。我们的第二个目标是揭示内源性大麻素水平的昼夜节律振荡、白细胞募集和梗死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节律振荡，在小鼠的黑暗期（=活动期）开始时具有最高的迁移率。这也是观察到内源性大麻素峰值水平的时候。因此，我们提出了一个与临床相关的问题，即一天中的时间是否决定了心肌梗死愈合的质量，以及这是否是由于内源性大麻素水平的昼夜变化。我们的研究结果将有望揭示新的治疗靶点，以改善心肌梗死后愈合，从而改善心脏功能。

项目成果

Pericardial Adipose Tissue Regulates Granulopoiesis, Fibrosis, and Cardiac Function After Myocardial Infarction

• DOI: 10.1161/circulationaha.117.028833
• 发表时间: 2018-02-27
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Horckmans, Michael;Bianchini, Mariaelvy;Steffens, Sabine
• 通讯作者: Steffens, Sabine

2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction

• DOI: 10.1093/cvr/cvy242
• 发表时间: 2018-09
• 期刊: Cardiovascular Research
• 影响因子: 10.8
• 作者: Maximilian J. Schloss;M. Horckmans;R. Guillamat-Prats;D. Hering;Estelle Lauer;S. Lenglet;C. Weber;Aurélien Thomas;S. Steffens

Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype

• DOI: 10.1093/eurheartj/ehw002
• 发表时间: 2017-01-14
• 期刊: EUROPEAN HEART JOURNAL
• 影响因子: 39.3
• 作者: Horckmans, Michael;Ring, Larisa;Steffens, Sabine
• 通讯作者: Steffens, Sabine