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

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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.