Pharmacological Tuning of Adenosine Signal Nuances Underlying Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) roughly represents half of the cardiac failure events in developed countries. The proposed ‘systemic microvascular paradigm’ has been used to explain HFpHF presentation heterogeneity. The lack of effective treatments with few evidence-based therapeutic recommendations makes HFpEF one of the greatest unmet clinical necessities worldwide. The endogenous levels of the purine nucleoside, adenosine, increase significantly following cardiovascular events. Adenosine exerts cardioprotective, neuromodulatory, and immunosuppressive effects by activating plasma membrane-bound P1 receptors that are widely expressed in the cardiovascular system. Its proven benefits have been demonstrated in preclinical animal tests. Here, we provide a comprehensive and up-to-date critical review about the main therapeutic advantages of tuning adenosine signalling pathways in HFpEF, without discounting their side effects and how these can be seized.

Adenosine A3 Receptor: From Molecular Signaling to Therapeutic Strategies for Heart Diseases

“…Endogenous adenosine can protect the overloaded heart against the development of pathological heart failure [ 74 ]. A study showed that mice deficient in extracellular adenosine production, stemming from a deletion in the CD73 gene, showed maladaptive tissue remodeling with the induction of cardiomyocyte hypertrophy, fibrosis, and left ventricular dilation and dysfunction in contrast to their wild-type counterparts under chronic systolic overload [ 75 ].…”

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

“…A 2B AR activation in muscle and brown fat had a beneficial effect on energy expenditure and increased muscle mass, suggesting the application of selective A 2B AR agonists that principally activate cAMP for treating obesity ( Gnad et al, 2020 ). A 2B AR activation also reduces cardiac fibrosis via the PKC δ to p38-MAPK pathway and protects the ischemic heart by stabilizing HIF-1 α ( Campos-Martins et al, 2021 ). Thus, translational opportunities are conceivable if selective and biased A 2B AR agonists could be developed for these signaling pathways.…”