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

Figures

• 

  FIGURE 1. Schematic representation of adenosine biosynthesis and complex signalling pathways induced by adenosine receptors activation. Adenosine is a purine nucleoside continuously generated from the catabolism of adenine nucleotides via a cascade of nucleotidases. Regarding the fate of intracellular adenosine, it may (preferentially) re-enter the purines savage pathway by intracellular phosphorylation via adenosine kinase (ADK) or it is inactivated to inosine by adenosine deaminase (ADA). The main source of adenosine results from the hydrolysis of S-adenosylhomocysteine (SAH) by SAH hydrolase. Under low oxygen availability and/or during high energy working loads, recruitment from ATP hydrolysis increases favouring intracellular adenosine accumulation, which promotes its diffusion to the extracellular medium via equilibrative nucleoside transporters (ENTs). Extracellular adenosine may also result from the extracellular breakdown of released adenine nucleotides, namely adenosine 5′-triphosphate (ATP), ADP (adenosine 5′-diphosphate), and AMP (adenosine 5′-monophosphate), by a cascade of ecto-nucleotidases bound to the plasma membrane. CD39 dephosphorylates ATP directly into AMP; the rate…

• 

  FIGURE 2. Schematic representation of cardiovascular effects of adenosine and related signalling pathways. In the cardiovascular system, adenosine exerts protective effects to control neuronal output (anti-adrenergic effect) and inflammation, while decreasing cardiac metabolism, myocardial contractility, impulse generation and conduction, and the coronary tone. These effects depend on the cellular type involved. The A1AR activation mediates cardioprotective effects by reversing cardiac hypertrophy/remodelling, improving mitochondrial function, enhancing SERCA2a activity and improving Ca2+ handling. The A1AR activation is also associated with an anti-ischemic effect by decreasing catecholamine release and by counteracting ß-adrenergic dysfunction. Activation of A2AAR attenuates cardiac inflammation, fibrosis and hypertrophy, while favoring vasodilation and angiogenesis. Despite the A2BAR-related vasodilation, angiogenesis and protection from ischemic preconditioning, conflicting evidence exist regarding the role of this receptor in fibrosis and related cardiac ischemic remodelling. Activation of A3AR is also associated with controversial results; this receptor mediates cardioprotective…

• 

  FIGURE 3. Schematic representation of adenosine receptors involvement in HFpEF pathophysiology. HFpEF is a complex clinical syndrome where comorbidities-induced systemic inflammation predispose and perpetuate microvascular dysfunction, as well cardiac structural and metabolic abnormalities. Overall, adenosine counteracts most of the pathophysiological features of this syndrome. These include 1) cardiac inflammation and microvascular dysfunction (via A2AR activation), 2) myocardial structural abnormalities (via A2AR and A1AR activation), and 3) energy metabolism and calcium handling (via A1AR activation). Conflicting evidence, however, exist regarding A2BAR-mediated cardioprotection, as this receptor has been implicated in both pro- and anti-fibrotic effects in the heart and lungs. Adenosine receptors also play important roles in cardiometabolic comorbidities related to HFpEF. Activation of A1AR improves the metabolic profile and induces renal afferent arteriole vasoconstriction, which can be protective when preservation of the glomerular architecture and function is needed. Stimulation of A2AAR and the A2BAR reduce lipolysis, but this beneficial effect may be partially counteracted by…