Cardioprotective crosstalk of adenosine and S1P in cardiac fibroblasts and cardiomyocytes

• Applicants: Dr. Julia Hesse; Dr. Petra Keul
• Subject Area: Cardiology, Angiology ; Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540017385

Background and previous work: Adenosine-A2BR and sphingosine 1-phosphate (S1P) signaling have individually been shown to promote cardiac healing after myocardial infarction (MI). While the cardioprotective role of A2BR has been known for quite some time, we have only very recently demonstrated, that elevation of S1P levels in mice improves cardiac function after MI. A direct interaction of A2BR and S1P has been reported in erythrocytes, where A2BR signaling increases the activity of the sphingosine kinase to produce S1P. To specifically address an A2BR–S1P crosstalk in the heart, we have re-analyzed existing single-cell RNA sequencing data and have carried out numerous experiments in cultured primary cardiac fibroblasts (CF) and cardiomyocytes (CM). Results obtained provide first evidence, that A2BR and S1P receptor subtypes are co-expressed in CF and CM post MI, that adenosine via A2BR and S1P reciprocally modulate each other’s metabolism and receptor expression, and that A2BR and S1P pathways interact and together regulate CF activation, cytokine expression and induction of cell-protective HIF-1α in CM. On the basis of these experiments, we propose a so far unrecognized cooperative role of A2BR and S1P signaling which modulates cellular responses in CF and CM and thereby promotes cardiac healing. Aims: Our aims comprise: (I) Definition of the mechanisms of the interaction of A2BR and S1P in CF and CM. (II) Characterization of the effects of A2BR–S1P interaction on cellular processes that are associated with post MI remodelling, such as CF activation, CM protection, and release of inflammatory cytokines, in vitro. (III) Exploration of the A2BR–S1P interaction in modulating the activity of CF and CM to promote post-MI healing in vivo. Work packages: In WP1, we will study in isolated CF and CM the reciprocal interaction of adenosine-A2BR and S1P pathways and their likely convergence into downstream signaling mediators such as HIF-1α signaling. In WP2, we will investigate the crosstalk and interdependence of A2BR and S1P signaling in remodeling-associated cellular activities in isolated CF and CM. In WP3, we will evaluate the A2BR–S1P crosstalk in modulating the activity of CF and CM to promote cardiac healing in vivo. Significance: This project will explore the mechanism and functional consequences of A2BR–S1P interaction on cellular as well as organ level in the post-MI heart. Understanding of this axis and its underlying processes will provide new mechanistic insights that are expected to lead to the development of novel therapeutic strategies to promote cardiac healing.

• DFG Programme: Research Grants