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.

Keywords: adenosine; adenosine receptor; cardiac comorbidities; cardiac fibrosis and hypertrophy; endothelial dysfunction; preserved ejection fraction heart failure.

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 limiting enzyme of the ecto-nucleotidase cascade is ecto-5′-nucleotidase/CD73, which dephosphorylates AMP to adenosine and inorganic phosphate. Extracellular adenosine levels are tightly regulated by cellular uptake via ENTs and/or by deamination into inosine by ADA. Adenosine activates 4 G protein-coupled receptor (GPCRs) known as P1 receptors (adenosine receptors (ARs): A₁AR, A_2AAR, A_2BAR, A₃AR). In brief, A₁AR and A₃AR are negatively coupled to adenylate cyclase (AC) through binding to G_i and G_o proteins, resulting in decreased intracellular cyclic AMP (cAMP) levels. Both A_2AAR and A_2BAR are coupled to G_s proteins and stimulate AC leading to increases in cAMP accumulation. Despite the canonical positive and negative coupling to the AC/cAMP system, A₁AR, A_2BAR, and A₃AR are also entitled to activate phospholipase C-beta (PLC- β) isoform, resulting in increased inositol 1,4,5-trisphosphate (IP3) and intracellular Ca²⁺ mobilization; intracellular Ca²⁺ and diacylglycerol (DAG) production contribute to stimulate Ca²⁺-dependent protein kinase C (PKC) and/or downstream Ca²⁺-dependent pathways. Adapted from (Borea et al., 2018). Green arrows and red bars indicate the effects induced or blocked by adenosine receptor activation, respectively. Illustration used elements from Servier Medical Art (http://smart.servier.com). AC, Adenosine cyclase; ADA, Adenosine deaminase; ADP, 5′adenosine diphosphate; ADK, Adenosine kinase; AMP, 5′-adenosine monophosphate; AR, Adenosine receptor; ATP, 5′-adenosine triphosphate; cAMP, cyclic AMP; CNT, Concentrative nucleoside transporter; DAG, diacylglycerol; ENT, Equilibrative nucleoside transporter; GCPR, G protein-coupled receptor; IP3, inositol 1,4,5-trisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC- ß, Phospholipase C- beta; SAH, S-adenosylhomocysteine.

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 A_2AAR attenuates cardiac inflammation, fibrosis and hypertrophy, while favoring vasodilation and angiogenesis. Despite the A_2BAR-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 effects by increasing angiogenesis and myocardial survival during reperfusion, but it may be deleterious by aggravating cardiomyocytes hypertrophy. Green arrows and red bars indicate effects induced or blocked by adenosine receptors activation, respectively. The red dashed line indicates that the effect is indirectly blocked by adenosine receptors activation. Illustration used elements from Servier Medical Art (http://smart.servier.com) AR, Adenosine receptor; AκT, Protein kinase B; Ca_v1 channel, L-type calcium channel subunit 1; DAG, diacylglycerol; EGR, Early Growth Response; EPAC, Exchange protein directly activated by cAMP; ERK, Extracellular signal-regulated protein kinase; GIRK and KIR3.1/3.4, G protein coupled inwardly rectifying K⁺ channels; GSK-3, Glycogen synthase kinase-3; HCN channels, Hyperpolarization-activated cyclic nucleotide-gated channel; HIF-1α, Hypoxia-inducible factor-alpha; IP₃, Inositol 1,4,5-trisphosphate; I_f , “funny” hyperpolarization-activated current; K_ATP, ATP-sensitive K⁺ channel; K_V, voltage-gated K⁺ channels; MAPK, Mitogen activated protein kinase; MEK, Mitogen-activated protein kinase; MPTP, Mitochondrial permeability transition pores; mTORC1, Rapamycin complex 1; NF-κB, Nuclear factor-κB; NO, Nitric oxide; Per2, Period 2; PI3K, Phosphoinositol-3 kinase; PKA, Protein kinase A; PKC, Protein kinase C; PLC, Phospholipase C; ROS, Reactive oxygen species; SERCA2a, Sarco/endoplasmic reticulum Ca²⁺-ATPase 2a.

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 A_2BAR-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 A_2AAR and the A_2BAR reduce lipolysis, but this beneficial effect may be partially counteracted by their action on skeletal muscles that contribute to insulin resistance. Activation of A_2AAR counteracts renal damage due to its ability to reduce fibrosis, independently of A₃AR and A_2BAR are active or not. The arrows and bars indicate the effects induced or blocked by adenosine receptor activation, respectively. Green = beneficial effect; Red = deleterious effect; Asterisk (*) = contradictory/conflicting data. Adapted from Lam et al., 2018 and Headrick et al., 2013. Illustration used elements from Servier Medical Art (http://smart.servier.com) ABCC4, ATP-binding cassette sub-family C member 4; AR, Adenosine receptor; cAMP, cyclic adenosine monophosphate; EPAC, Exchange factor directly activated by cAMP; FFA, Free fatty acid; GLUT, Glucose transporter; MAPK, Mitogen activated protein kinase; MPTP, Mitochondrial permeability transition pores; NO, Nitric oxide; PKA, Protein kinase A; PKC, Protein kinase C; PMN, Polymorphonuclear leukocytes; SERCA2a, Sarco/endoplasmic reticulum Ca²⁺-ATPase 2a; a-SMA, Alpha-smooth muscle actin; VSMC, Vascular smooth muscle cell.