Targeting ADORA-PDE10 cAMP Microdomain: A Novel Therapeutic Approach for Pulmonary Hypertension

Despite substantial advancements in the treatment of pulmonary arterial hypertension (PAH), obstacles remain in achieving optimal outcomes. In this study, we focus on understanding the therapeutic effect of targeting the ADORA1/PDE10A-regulated cyclic AMP (cAMP) microenvironment in treating pulmonary hypertension. Screening of differentially expressed adenosine receptors in samples derived from healthy individuals and patients with idiopathic pulmonary arterial hypertension (IPAH) showed that ADORA1 expression was significantly upregulated under disease conditions. Functional studies revealed that, upon ADORA1 inhibition, donor hPASMCs showed anti-proliferative, pro-apoptotic features and increased intracellular cAMP levels. Surprisingly, the same effects were not replicated in IPAH PASMCs, suggesting the presence of another cAMP regulatory factor in close proximity to ADORA1 in IPAH PASMCs. To investigate this point, we performed protein-protein interaction studies in IPAH PASMCs and found that Phosphodiestrase 10A (PDE10A) co-localizes with ADORA1 under disease conditions. Moreover, we observed that ADORA1 and PDE10A form a regulatory complex in the A kinase anchoring protein 5 (AKAP5) microdomain. Silencing or dual inhibition of both ADORA1 and PDE10A in IPAH PASMCs induced anti-proliferative and pro-apoptotic effects with increased intracellular cAMP levels. To investigate the effects of the dual inhibitor in vivo, we administered it to both MCT and Sugen5416/hypoxia (SuHx) rat models of PAH, showing improved right ventricle function, reduced pulmonary vascular resistance and decreased lung vascular remodeling. In conclusion, we provide evidence that dual pharmacological targeting of ADORA1 and PDE10A has high therapeutic potential against PAH.