Analyses of the serotonin receptor 5-HT7 for myocardial remodeling and depression in response to myocardial infarction

心力衰竭患者更常受到重度抑郁症（MDD）的影响。反之亦然，MDD代表心血管疾病（包括心肌梗死（MI））的独立风险因素。虽然MDD和MI之间联系的确切性质尚未确定，但5-羟色胺系统的失调可能与这两种疾病的病因有关。5-羟色胺参与多种生物学过程，通过7种不同的5-羟色胺受体家族发挥作用，这些受体具有高度的细胞和发育特异性表达模式，我们的数据揭示了5-HT 7 R介导的5-羟色胺信号转导与免疫细胞的形态和运动的调节在体外和体内的相关性，表明5-HT 7 R作为炎症反应的调节剂。我们的初步数据显示，与野生型小鼠（WT）相比，5-HT 7 R（5-HT 7 R-KO）系统敲除小鼠在MI后显示出更好的存活率。进一步分析显示，5-HT 7 R-KO小鼠在梗塞心脏中显示较少的白细胞，并且在巨噬细胞中，与促炎性M1巨噬细胞相比，抗炎性M2巨噬细胞的百分比在5-HT 7 R-KO小鼠中高于WT小鼠。与5-HT 7 R-KO动物相比，这些发现沿着WT小鼠的组织完整性丧失以及死亡率增加。有趣的是，我们观察到在单核细胞分化为巨噬细胞期间5-HT 7 R的上调，并且在原代人单核细胞中，我们发现5-HT 7 R的药理学抑制降低了促炎细胞因子的表达。这些数据使我们假设巨噬细胞上的5-HT 7 R在梗塞心脏的炎症过程中起特定作用。此外，由于5-HT 7 R拮抗剂被用于治疗抑郁症和其他精神疾病，我们推测，全身减少5-HT 7 R不仅可以改善心肌梗死后的心脏结局，而且还可以减少抑郁症作为心肌梗死的危险因素。在本资助申请中，我们将在WT和5-HT 7 R-KO小鼠、分离的原代小鼠和人单核细胞和巨噬细胞以及单核细胞系中研究这些假设。

Patients with heart failure are more frequently affected by the major depressive disorder (MDD). Vice versa, MDD represents an independent risk factor for cardiovascular disorders, including myocardial infarction (MI). Although the precise nature of the link between MDD and MI has not yet been established, dysregulation of the serotonin system might be involved in the etiology of both diseases. Serotonin is involved in multiple biological processes and acts through seven different serotonin receptor families with highly cell and development specific expression patterns.Our data revealed a relevance of 5-HT7R -mediated serotonin signaling for the regulation of immune cells morphology and motility both in vitro and in vivo, suggesting that 5-HT7R acts as a regulator of inflammatory responses. Inflammation plays a crucial role for healing and remodeling of the infarcted heart with monocytes and macrophages being crucial players.Our preliminary data shown, that mice with a systemic knockout for the 5-HT7R (5-HT7R–KO) display a better survival rate after MI compared to wild type mice (WT). Further analyses revealed that 5-HT7R–KO mice display less leukocytes in the infarcted heart and among macrophages, the percentage of anti-inflammatory M2 macrophages compared to pro-inflammatory M1 macrophages was higher in 5-HT7R-KO compared to WT mice. These findings went along with a loss of tissue integrity as well as increased mortality rate in WT mice in comparison to 5-HT7R-KO animals. Interestingly, we observed an upregulation of the 5-HT7R during the differentiation of monocytes to macrophages and in primary human monocytes we found that pharmacological inhibition of the 5-HT7R reduced the expression of pro-inflammatory cytokines. These data lead us to the hypothesis that the 5-HT7R on macrophages plays a specific role in inflammatory processes in the infarcted heart. In addition, since 5-HT7R antagonists are used to treat depression and other psychiatric disorders, we hypothesize that a systemic reduction of 5-HT7R may not only improve cardiac outcome after MI but may also reduce depression as a risk factor for MI. In the present grant application we will investigate these hypotheses in WT and 5-HT7R-KO mice and in isolated primary mouse and human monocytes and macrophages as well as in monocytic cell lines.