Unveiling the role of G-protein-coupled receptors in Pulmonary Hypertension

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Unveiling the role of the G protein-coupled receptors GPRC5B, P2Y2, GPR4, and GPR21 in the development and treatment of pulmonary hypertension. G-protein coupled receptors (GPCRs) play a prominent role in the therapy of cardiopulmonary diseases and, with over 1000 different members, represent the largest protein superfamily. Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vessels that alters all vascular layers and increases the pulmonary artery pressure (PAP) leading in late stages, if not treated, to the right heart failure and consequently the death. Numerous drugs have been developed in the past to act as agonists or antagonists of GPPCRs in PAH. In initial studies on human cells and tissues from PAH patients, we identified new differentially regulated GPCRs, the role of which is to be further investigated in this application. Using GPCR-specific microarrays and sequencing studies, we identified four new GPCRs (GPRC5B, GPR4, GPR21, and P2Y2) and three G proteins (GNA11, GNA14, and GNG2) that are significantly changed in patients and yet have not been investigated in PAH research. So far, we have carried out our initial studies on the role of the purinergic receptor P2Y2 in human pulmonary arterial endothelial and smooth muscle cells (HPAECs or HPASMCs). The endothelial P2Y2 receptor is involved in increased NO secretion, whereas the activation of P2Y2 in the pulmonary smooth muscle cells with its specific agonist (MRS2768) attenuates the proliferation rate of the IPAH-HPASMCs and should be therefore further investigated. The function of the receptors GPRC5B, GPR4, and GPR21 has only recently been demonstrated and their specific ligands, which have not yet been investigated in the field of pulmonary hypertension, are available for further investigations (compound 3b and GRA2). The four promising GPCRs and their ligands (GPRC5B without ligands, GPR4 and its compound 3b, GPR21 and its ligand GRA2 as well as P2Y2 and its ligand MRS2768) in addition to GNA11, GNA14, and their ligands (FR900359, YM-254890, and WU-07047) will be investigated in invitro and ex-vivo (isolated intrapulmonary arterial rings, isolated perfused mouse lungs). The in-vivo approach will consider endothelial- and smooth muscle-specific induced knockout mice of P2Y2 and GPRC5B to figure out their role in the different cell layers of pulmonary vessels. In summary, due to our best knowledge, this study would be the first comprehensive study for PAH-G proteins and PAH-GPCRs towards more understanding, better conditions, and new treatment for PAH patients.